[go: up one dir, main page]

TR201806309A2 - Solid oral pharmaceutical compositions of dabigatran etexilate - Google Patents

Solid oral pharmaceutical compositions of dabigatran etexilate Download PDF

Info

Publication number
TR201806309A2
TR201806309A2 TR2018/06309A TR201806309A TR201806309A2 TR 201806309 A2 TR201806309 A2 TR 201806309A2 TR 2018/06309 A TR2018/06309 A TR 2018/06309A TR 201806309 A TR201806309 A TR 201806309A TR 201806309 A2 TR201806309 A2 TR 201806309A2
Authority
TR
Turkey
Prior art keywords
weight
formulation
acid
capsule
pellets
Prior art date
Application number
TR2018/06309A
Other languages
Turkish (tr)
Inventor
Uraz Ezel
Palantöken Arzu
Türkyilmaz Ali̇
Gülkok Yildiz
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=64559741&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=TR201806309(A2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi filed Critical Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority to EA201992644A priority Critical patent/EA201992644A1/en
Priority to BR112019023781-0A priority patent/BR112019023781A2/en
Priority to EP18811675.0A priority patent/EP3634388A2/en
Priority to NZ759901A priority patent/NZ759901A/en
Priority to AU2018293361A priority patent/AU2018293361B2/en
Priority to PCT/TR2018/050221 priority patent/WO2019004980A2/en
Publication of TR201806309A2 publication Critical patent/TR201806309A2/en
Priority to EP19848668.0A priority patent/EP3787624A4/en
Priority to PCT/TR2019/050292 priority patent/WO2020032885A2/en
Priority to CONC2019/0013649A priority patent/CO2019013649A2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention relates to solid oral pharmaceutical compositions, comprising dabigatran etexilate in the of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof.

Description

TARIFNAME DABIGATRAN ETEKSILAT IÇEREN KATI ORAL FARMASÖTIK KOMPOZISYONLAR Bulusun Alani . DESCRIPTION SOLID ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING DABIGATRAN ETEXSILAT Field of Invention.

Mevcut bulus, birinci kapsül ve birinci kapsülün içerisine yerlestirilmis ikinci kapsülden olusan bir dozaj birimi formunda, dabigatran eteksilat serbest baz n' veya dabigatran eteksilatn farmasötik açLdan kabul edilebilir tuzlartnm polimorflarmL, solvatlarnm hidratlarn; veya esterlerini ve en az bir organik asit içeren kat oral farmasötik kompozisyonlarlyla ilgilidir. The present invention consists of a first capsule and a second capsule placed inside the first capsule. dabigatran etexilate free base n' or dabigatran etexilate in a dosage unit form polymorphs of pharmaceutically acceptable salts, hydrates of solvates; or It relates to solid oral pharmaceutical compositions containing esters and at least one organic acid.

Teknigin Bilinen Durumu Dabigatran etkili , tersinir, tek degerlikli (univalent) bir direkt trombin inhibitörüdür. Dabigatran, aminometil] benzimidazoI-5-il karboksilik asit-N-(2-pridiI)-N-(2 etoksikarboniletil)amid adi alt nda trombin inhibe edici etkiye ve trombin süresini uzatC' etkiye sahip bilesikler olarak açklanmßtr. State of the Art Dabigatran is an effective, reversible, univalent direct thrombin inhibitor. dabigatran, aminomethyl] benzimidazol-5-yl carboxylic acid-N-(2-pyridyl)-N-(2 ethoxycarbonylethyl)amide name Compounds with a thrombin inhibitory effect and a thrombin time prolonging effect explained.

Yeni bir direkt trombin inhibitörü olan dabigatran eteksilat, dabigatranm ön ilacîve peptit olmayan trombin inhibitörüdür. Yap Sal formülü sudur: Dabigatran, Boehringer Ingelheim firmas na ait Pradaxa ticari ismi altmda dabigatran eteksilat mesilat olarak mevcut olup, non-valvüler atriyal fibrilasyonlu hastalarda inme ve sistemik embolizm riskinin azaltllmas nda kullan Imaktad r. Dabigatran etexilate, a new direct thrombin inhibitor, is a prodrug and peptide of dabigatran. It is a non-thrombin inhibitor. The Yap Sal formula is: Dabigatran is a dabigatran etexilate under the trade name Pradaxa of Boehringer Ingelheim. It is available as mesylate and is present in patients with non-valvular atrial fibrillation for stroke and systemic It is used to reduce the risk of embolism.

Dabigatran eteksilatn sudaki çözünürlügü 1.8 mg/mL olup, ortamn pH'slna baglmlldm. suda çözünürlülügü >1g/250ml olan, dabigatran eteksilat ve organik asit içeren bir tablet formülasyonu önerilmektedir. The solubility of dabigatran etexilate in water is 1.8 mg/mL and it depends on the pH of the medium. A tablet containing dabigatran etexilate and organic acid, with a water solubility >1g/250ml formulation is recommended.

Dabigatran eteksilat aynEzamanda asidik ortamda daha az stabildir. Stabilite probleminin önüne geçmek için önceki teknikte birçok çözüm önerilmistir. EP2740471 B1 numaral;patentte inorganik asit içeren bir çekirdek, etkin madde katmani .ve inorganik asit içeren çekirdek ile etkin madde katmani aras'nda yer alan bir izolasyon katmanlrtdan olusan bir farmasötik kompozisyon açklanmaktadT. EP2588090A2 numaraI* patent basvurusunda, küresel çekirdek üzerine kaplanmls bir tartarik asit katman', tartarik asit katman üzerinde bir izolasyon katmanzve izolasyon katmanLüzerinde dabigatran eteksilat içeren bir katmanjhtiva eden bir patent basvurusunda, dabigatran içeren tablet formunda birinci bilesen ile organik asit içeren kapsül formunda ikinci bilesenden olusan bir farmasötik kompozisyon açlklanmaktadlr. Dabigatran etexilate is also less stable in an acidic environment. stability problem Many solutions have been proposed in the prior art to prevent EP2740471 B1 patented with a core containing inorganic acid, a layer of active ingredient and a core containing inorganic acid a pharmaceutical consisting of an insulating layer between the active ingredient layer the composition is explained. In patent application EP2588090A2*, global a layer of tartaric acid coated on the core, an isolation on the tartaric acid layer layerzand insulating layerL, containing a layer containing dabigatran etexilate In the patent application, the first component in tablet form containing dabigatran and organic acid containing A pharmaceutical composition comprising the second component in capsule form is disclosed.

Teknikte hala, dabigatran eteksilath stabil, uygun maliyetli, hazîlanmas *kolay, arzu edilen in- vitro saIIJmnEveren, daha iyi bir dissolüsyon profiline ve biyoyararlanîna sahip alternatif kompozisyonlarlrn hazrlanmastna ihtiyaç duyulmaktadm. Iç içe yerlestirilmis kapsül teknolojisi kullanarak organik asit içeren formülasyonu, dabigatran eteksilat içeren formülasyondan amianm kolay yolunu bulduk. Buldugumuz bu yol ile aynHzamanda yüksek stabilite ve iyilestirilmis dissolüsyon profili elde edilmektedir. Still in the art, dabigatran extract is stable, cost-effective, easy to prepare, desired injectable. in vitro saIIJmnEveren, an alternative with a better dissolution profile and bioavailability I was needed to prepare compositions. Nested capsule technology using the organic acid-containing formulation from the dabigatran etexilate-containing formulation. We found the easy way to amian. With this path we found, at the same time high stability and improved dissolution profile is obtained.

Bulusun Ayr'ntlll Açiklamasu Mevcut bulusun esas amac , bir birim dozaj formunda dabigatran eteksilat serbest bazln veya dabigatran eteksilat n farmasötik açldan kabul edilebilir tuzlar nl, polimorflarin ,l solvatlar nl, hidratlarln' ;veya esterlerini ve en az bir organik asit içeren, iyi stabilite ve etkin dissolüsyon profiline sahip katîoral farmasötik kompozisyonlar saglanmasdî. Detailed Description of the Invention The main purpose of the present invention is to provide dabigatran etexilate free base or pharmaceutically acceptable salts of dabigatran etexilate nl, polymorphs l solvates nl, Good stability and effective dissolution containing hydrates or esters and at least one organic acid Oral pharmaceutical compositions with a profile of .

Mevcut bulusun diger bir amac,, yüksek biyoyararlantma sahip dabigatran eteksilat içeren stabil bir formülasyon elde edilmesidir. Another object of the present invention is to contain high bioavailability dabigatran etexilate. to obtain a stable formulation.

Mevcut bulusun bir baska amacî bahsedilen farmasötik kompozisyonun hazFrIanmasîçin kolay ve uygun maliyetli bir prosesin saglanmastdîj. Another object of the present invention is to prepare said pharmaceutical composition. providing an easy and cost-effective process.

Bir uygulamaya göre, bahsedilen farmasötik kompozisyon, bir direkt trombin inhibitörü serbest bazinl iveya söz konusu inhibitörün farmasötik aç'dan kabul edilebilir tuzlar ni , polimorflar nl, solvatlar nl, hidratlarln veya esterlerini ve en az bir organik asit içermekte olup; söz konusu kompozisyon, birinci kapsül ve birinci kapsülün içerisine yerlestirilmis ikinci bir kapsülden olusan bir dozaj birimi formundad r. According to one embodiment, said pharmaceutical composition is a direct thrombin inhibitor free baseline or pharmaceutically acceptable salts of said inhibitor, polymorphs nl, solvates include nl, its hydrates or esters and at least one organic acid; aforementioned The composition consists of a first capsule and a second capsule placed inside the first capsule. It is in the form of a dosage unit formed.

Burada kullantldîgîsekliyle "birim dozaj formu" terimi, birinci kapsül ve ikinci kapsülden olusan iç içe yerlestirilmis bir kapsül teknolojisi anlam'na gelmekte olup; burada ikinci kapsül, birinci kapsülün içerisinde yer almaktad r. Birinci kapsül, birinci formülasyonu içermekte olup; söz konusu birinci formülasyon direkt trombin inhibitörü veya organik asit olabilir. Ikinci kapsül, ikinci formülasyonu içermekte olup; söz konusu ikinci formülasyon direkt trombin inhibitörü veya organik asit olabilir. As used herein, the term "unit dosage form" includes a first capsule and a second capsule. It means a nested capsule technology; here is the second capsule, the first contained in the capsule. The first capsule contains the first formulation; promise The first formulation may be a direct thrombin inhibitor or an organic acid. second capsule, comprising the second formulation; said second formulation direct thrombin inhibitor or organic acid.

Burada kullan ldlgl lhaliyle “dabigatran eteksilat serbest baz ” terimi, aktif klSmn diger formlar rii:, özellikle asit ilaveli tuzlar bar nd rimayan dabigatran eteksilat anlam na gelmektedir. The term “dabigatran etexilate free base” as used herein refers to the other Forms rii: means dabigatran etexilate, especially free of acid addition salts.

Mevcut bulusun bu uygulamasîta göre, birinci kapsül, birinci ve ikinci kapsül arasmda yer alan birinci formülasyonu, ikinci kapsül ise ikinci formülasyonu içermektedir. According to this embodiment of the present invention, the first capsule is located between the first and the second capsule. contains the first formulation and the second capsule contains the second formulation.

Mevcut bulusun bu uygulamalarmia göre, tek bir dozaj biriminde birbirleriyle geçimsiz formülasyonlarn bir kombinasyonu saglanmaktad'n. Iç içe yerlestirilmis kapsüllerin hazTlanmasýdaha kolaydT ve önceki teknikte sfklkla kullan Tan izolasyon katman ?gerekliligini ortadan kaldîrî. According to these embodiments of the present invention, they are incompatible with each other in a single dosage unit. A combination of formulations is provided. of nested capsules It is easier to prepare and can be used frequently in the previous technique. eliminated.

Burada kullan Idîgl 'sekliyle "geçimsiz formülasyonlar" terimi, direkt trombin inhibitörü serbest bazini lveya söz konusu inhibitörün farmasötik aç olan kabul edilebilir tuzlari, polimorflar, solvatlar, hidratlar veya esterlerini veya bir organik asit içeren birinci ve ikinci formülasyon anlam na gelmektedir. As used herein, the term "incompatible formulations" refers to direct thrombin inhibitor free base 1 or pharmaceutically acceptable salts of said inhibitor, polymorphs, first and second formulation containing solvates, hydrates or esters or an organic acid it means.

Mevcut bulusun bu uygulamalarma göre birinci formülasyon ve ikinci formülasyon, mini tabletler veya granüller veya pelletler veya toz veya boncuklar veya kapsüller veya bunlarî'i karstmlarjormunda olabilir. According to these embodiments of the present invention, the first formulation and the second formulation are mini tablets or granules or pellets or powder or beads or capsules or these may be in the karstmlarform.

Mevcut bulusun bir uygulamas'na göre, birinci formülasyon, direkt trombin inhibitörü serbest bazTiTiveya söz konusu inhibitörün farmasötik açdan kabul edilebilir tuzlar'î polimorflarî solvatlar: hidratlarîveya esterlerini veya bir organik asit içermektedir. According to one embodiment of the present invention, the first formulation is a direct thrombin inhibitor free polymorphs of the base or pharmaceutically acceptable salts of said inhibitor solvates: containing hydrates or esters or an organic acid.

Mevcut bulusun bir uygulamasina göre, ikinci formülasyon, direkt trombin inhibitörü serbest bazini lveya söz konusu inhibitörün farmasötik aç dan kabul edilebilir tuzlari, polimorflar, solvatlar , hidratlar `veya esterlerini veya bir organik asit içermektedir. According to one embodiment of the present invention, the second formulation is a direct thrombin inhibitor free base 1 or pharmaceutically acceptable salts of said inhibitor, polymorphs, solvates, hydrates or esters, or an organic acid.

Mevcut bulusun bir uygulamasina göre, bahsedilen farmasötik kompozisyon birinci kapsül ve birinci kapsülün içerisine yerlestirilmis ikinci bir kapsülden olusan bir dozaj birimi formunda olup, bahsedilen birinci formulasyon birinci kapsül ve ikinci kapsül arasîîida ve bahsedilen ikinci formulasyon ikinci kapsül içerisinde yer ali), söz konusu birinci formulasyon veya söz konusu ikinci formulasyon bir direkt trombin inhibitörü serbest baz,Veya söz konusu inhibitörün farmasötik açldan kabul edilebilir tuzlari,i polimorflar.,i solvatlar.,i hidratlari iveya esterleri veya en az bir organik asit içermektedir. According to one embodiment of the present invention, said pharmaceutical composition is a first capsule and in the form of a dosage unit consisting of a second capsule placed inside the first capsule wherein said first formulation is between the first capsule and the second capsule and said the second formulation is contained in the second capsule), said first formulation or said said second formulation is a direct thrombin inhibitor free base, or said inhibitor pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters or contains at least one organic acid.

Mevcut bulusun bir uygulamasina göre, bahsedilen direkt trombin inhibitörü, serbest baz formunda veya farmasötik açdan kabul edilebilir tuzlar+ polimorflausolvatlar; hidratlar'sVeya esterleri formunda olan dabigatran eteksilatt n. According to one embodiment of the present invention, said direct thrombin inhibitor is free base in the form of or pharmaceutically acceptable salts + polymorphlausolvates; hydrates's or dabigatran etexilate n.

Uygun organik asit, en az bir karboksilik grup içermektedir. Uygun organik asit, bunlarla sn ril i olmamasýkayd yla sitrik asit, tartarik asit, galik asit, orotik asit, p-kumarik asit, hipürik asit, ferulik asit, vanilik asit, fumarik asit, maleik asit, süksinik asit, sitrik asit, malik asit, glutamik asit, aspartik asit, oksalik asit, Iaktik asit, formik asit, asetik asit, propionik asit, kaproik asit, benzoik asit, karbonik asit, adipik asit veya bunlarmi kari,s;mlarii)labilir. A suitable organic acid contains at least one carboxylic group. Suitable organic acid, limited with provided that there is no citric acid, tartaric acid, gallic acid, orotic acid, p-coumaric acid, hipuric acid, ferulic acid, vanillic acid, fumaric acid, maleic acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid, oxalic acid, lactic acid, formic acid, acetic acid, propionic acid, caproic acid, benzoic acid, carbonic acid, adipic acid or a mixture of these can be used.

Mevcut bulusun bir uygulamasîta göre, bahsedilen organik asit, sitrik asit veya tartarik asit veya bunlarm karßînlarîlî. According to one embodiment of the present invention, said organic acid is citric acid or tartaric acid. or against them.

Organik asit, dabigatran eteksilatin yüksek biyoyararlanim ve çözünürlük göstermesinde önemli bir isleve sahiptir. Ancak, yüksek miktarlarda kullanilan organik asit, hasta üzerinde geçimsizlige neden olabilir veya organik asidin intrinsik özelliklerinden dolayi formulasyonlarda kullanilacak ilac n miktarin isin rlayabilir. Bahsedilen farmasötik kompozisyonda kullan Iacak direkt trombin inhibitörünün ve organik asidin miktarlar'nin belirlenmesinde, söz konusu nedenler dikkate almmal dm. The organic acid, dabigatran etexilatine, shows high bioavailability and solubility. has an important function. However, organic acid used in high amounts can affect the patient. may cause incompatibility or be used in formulations due to the intrinsic properties of the organic acid. It may limit the amount of the drug to be used. To be used in said pharmaceutical composition in determining the amounts of direct thrombin inhibitor and organic acid, reasons should not be taken into account.

Mevcut bulusun bir uygulamasina göre, direkt trombin inhibitörünün organik aside agmlikça oran , 0.6 ile 8.0 aras nda, tercihen 1.0 ile 5.0 arasindadir. According to one embodiment of the present invention, the aggregation of the direct thrombin inhibitor into organic acid. the ratio is between 0.6 and 8.0, preferably between 1.0 and 5.0.

Mevcut bulusun bir uygulamasha göre, dabigatran eteksilatin sitrik aside agirlkça oran I` 0.6 ile 8.0 arasîtda, tercihen 1.0 ile 5.0 arasLîidadLîî. According to one embodiment of the present invention, the weight ratio of dabigatran etexilate to citric acid is I` 0.6 between 1.0 and 8.0, preferably between 1.0 and 5.0.

Mevcut bulusun bir uygulamasina göre, dabigatran eteksilatin tartarik aside ag'rlikça oran ,0.6 ile 8.0 aras nda, tercihen 1.0 ile 5.0 arasindadiri. According to one embodiment of the present invention, the weight ratio of dabigatran etexilate to tartaric acid is 0.6 between 1.0 and 8.0, preferably between 1.0 and 5.0.

Bir uygulamaya göre, bahsedilen kompozisyon, dolgu maddeleri, dagltlollar, seyrelticiler, dispersiyon ajanlar, baglayoîlar, Iubrikanlar, glidantlar, plastiklestiriciler, koruyucular, tatlandîlöîlar, aroma vericiler, eritici bilesenler, renklendiriciler, çözücüler veya bunlarn karîsmtlarîidan seçilen en az bir farmasötik olarak kabul edilebilir yardI'nc: madde içermektedir. According to one embodiment, said composition may contain fillers, dispersants, diluents, dispersing agents, binders, lubricants, glidants, plasticizers, preservatives, flavorings, flavorings, solvents, colorants, solvents or their at least one pharmaceutically acceptable excipient selected from its mixtures: substance contains.

Uygun dolgu maddeleri, bunlarla sin'nl olmamas kaydiyla, Iaktoz, seker, nisasta, modifiye Uygun dagtolar, bunlarla snrlL olmamasLl kaydLyla, çapraz bagl; polivinil pirolidon (krospovidon), povidon, çapraz bagl' karboksimetil selüloz (kroskarmelloz sodyum), düsük ikameli hidroksipropil selüloz, prejelatinize nisasta, sodyum karboksimetil selüloz, kalsiyum karboksimetil selüloz, karboksimetil selüloz, dokusat sodyum, guar zamk ,l poliakrilat potasyum, sodyum aljinat, mTsT nisastas: sodyum nisasta glikolat, aljinik asit, aljinatlar, iyon degistirici reçineler, magnezyum alüminyum silika, sodyum dodesil sülfat, poloksamer, sodyum glisin karbonat, sodyum Iauril sülfat veya bunlarn karSLîtnlar:olabilir. Suitable fillers, provided that they are not compatible with them, are lactose, sugar, starch, modified Suitable mountains, but not limited to, are cross-linked; polyvinyl pyrrolidone (crospovidone), povidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), low substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, 1 polyacrylate potassium, sodium alginate, mTsT starch: sodium starch glycolate, alginic acid, alginates, ion modifier resins, magnesium aluminum silica, sodium dodecyl sulfate, poloxamer, sodium glycine carbonate, sodium lauryl sulfate or their mixtures.

Uygun seyrelticiler, bunlarla 3 n rl, 'olmamas kayd yla, mikrokristalin selüloz, mannitol, spreyle kurutulmus mannitol, Iaktoz, nisasta, dekstroz, sukroz, fruktoz, maltoz, sorbitol, ksilitol, inositol, kaolin, inorganik tuzlar, kalsiyum tuzlarî polisakkaritler, dikalsiyum fosfat, sodyum klorür, dekstratlar, laktitol, maltodekstrin, sukroz-maltodekstrin karEsEn:trehaloz, sodyum karbonat, sodyum bikarbonat, kalsiyum karbonat veya bunlar n karls'mlar' olabilir. Appropriate diluents, provided they are not 3 types, include microcrystalline cellulose, mannitol, spray dried mannitol, lactose, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin compounds: trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.

Uygun dispersiyon ajanlar, bunlarla sin rl lolmamas ikayd yla kalsiyum silikat, magnezyum alüminyum silikat veya bunlarn kar s mlarl olabilir. Suitable dispersing agents include, but are not limited to, calcium silicate, magnesium aluminum silicate or mixtures thereof.

Uygun baglayîzllar, bunlarla smîlîolmamasîkaydwla polivinilpirolidon, karnauba mumu, pullulan, gliseril behenat, polikarbofil, polivinil asetat ve bunun kopolimerleri, selüloz asetat ftalat, hidroksipropil nisasta, sekerler, tragakant zamk-,lsetostearil alkol, arapzamk, polietilen glikol, polivinil alkol, nisasta, prejelatinize nisasta, glikoz, glikoz surubu, dogal zamklar, sukroz, sodyum aljinat, hidroksietil selüloz, sodyum karboksimetil selüloz, karboksimetil selüloz kalsiyum, etil selüloz, mikrokristalin selüloz, hidroksipropil metil selüloz, hidroksipropil selüloz, karboksi metil selüloz, metil selüloz gibi selüloztürevleri, karragenan, guar zamkL: polimetakrilatlar, metakrilat polimerler, kollajenler, jelatin, agar gibi proteinler, aljinat, ksantan zamk', hiyalüronik asit, pektin, polisakkaritler, karbomer, poloksamer, poliakrilamit, alüminyum hidroksit, Iaponit, bentonit, polioksietilen-alkil eter, polidekstroz, polietilen oksit veya bunlar n kar slmlar olabilir. Suitable binders, not being associated with them, are polyvinylpyrrolidone, carnauba wax, pullulan, glyceryl behenate, polycarbophil, polyvinyl acetate and its copolymers, cellulose acetate phthalate, hydroxypropyl starch, sugars, tragacanth gum-, cetostearyl alcohol, gum arabic, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, cellulose derivatives such as carboxymethyl cellulose, methyl cellulose, carrageenan, guar gumL: polymethacrylates, methacrylate polymers, collagens, gelatin, proteins such as agar, alginate, xanthan gum', hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, Iaponite, bentonite, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or these there may be snowfalls.

Uygun Iubrikanlar , bunlarla sin rl olmamas kaydlyla, magnezyum stearat, kalsiyum stearat, çinko stearat, talk, mumlar, borik asit, hidrojenlenmis bitkisel yag, sodyum klorat, magnezyum asidi, fumarik asit, gliseril palmito stearat, sodyum stearil fumarat, sodyum Iauril sülfat veya Uygun glidantlar, bunlarla smrl'îolmamas'*kaydlyla, kolloidal silikon dioksit, talk, alüminyum silikat, silika veya bunlar n kar s mlarl olabilir. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium acid, fumaric acid, glyceryl palmito stearate, sodium stearyl fumarate, sodium lauryl sulfate or Suitable glidants, provided they are not limited to, colloidal silicon dioxide, talc, aluminum silicate, silica or a mixture of these.

Uygun plastiklestiriciler, bunlarla sin rll lolmamasl l kayd yla, farkli l molekül ag rllklar nda polietilen glikolleri, propilen glikol veya bunlarin kar slmlar olabilir. Suitable plasticizers are available in different molecular weights, provided that they are not limited thereto. polyethylene glycols, propylene glycol or mixtures thereof.

Uygun koruyucular, bunlarla snrlîolmamasîkaydyla metil paraben ve propil paraben ve tuzlarnîsodyum, potasyum gibi), sodyum benzoat, sitrik asit, benzoik asit, bütil hidroksitolüen ve bütil hidroksianisol veya bunlarît karSInlar:olabilir. Suitable preservatives include, but are not limited to, methyl paraben and propyl paraben and salts such as sodium, potassium), sodium benzoate, citric acid, benzoic acid, butyl hydroxytoluene and butyl hydroxyanisole or mixtures thereof.

Uygun tatlandlrcllar, bunlarla Sl'llfll .olmamasilkaydyla aspartam, potasyum asesülfam, sodyum sakkarinat, neohesperidin dihidrokalkon, sukraloz, sakkarin, sukroz, glikoz, Iaktoz, fruktoz gibi sekerler ve mannitol, sorbitol, ksilitol, eritritol gibi seker alkolleri veya bunlarTt karîsmtlarîolabilir. Suitable sweeteners are aspartame, potassium acesulfame, sodium saccharinate, neohesperidin dihydrochalcone, sucralose, saccharin, sucrose, glucose, Iactose, sugars such as fructose and sugar alcohols such as mannitol, sorbitol, xylitol, erythritol or theseTt they may be racial.

Uygun aroma vericiler , bunlarla 5 n nl olmamasi kaydiyla, mentol, nane, tarçln, çikolata, vanilya ve kiraz, portakal, çilek, üzüm, siyah frenk üzümü, ahududu, muz, klrm zl meyveler, yabani çilekler vs. gibi meyve özleri veya bunlarin kar slmlar olabilir. Suitable flavorings include menthol, mint, cinnamon, chocolate, vanilla and cherry, orange, strawberry, grape, black currant, raspberry, banana, red berries, wild strawberries etc. such as fruit extracts or their mixtures.

Uygun eritici bilesenler, gelucire (stearil makrogolgliserit), poloksamer (polioksietilen- polioksipropilen blok kopolimeri), polietilen glikol, povidon, soluplus, katyonik metakrilat, kopovidon, metakrilik asit kopolimerleri, selüloz asetat ftalat, asetilat monogliserid, butil ptalbulbütil glikolat, dibutil tartrat, dietil ftalat, dimetil ftalat, etil ftaliletil glikolat, gliserin, propilen glikol, triasetin, triasetin sitrat, tripropionin veya bunlarin karsmlarlnln aras ndan seçilmektedir. Suitable melting components are gelucire (stearyl macrogolglyceride), poloxamer (polyoxyethylene- polyoxypropylene block copolymer), polyethylene glycol, povidone, soluplus, cationic methacrylate, copovidone, methacrylic acid copolymers, cellulose acetate phthalate, acetylate monoglyceride, butyl phthalbulbutyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalylethyl glycolate, glycerine, propylene glycol, triacetin, triacetin citrate, tripropionine or mixtures thereof. is selected.

Uygun renklendirme maddeleri, bunlarla sîttîlîolmamas :kayd Sila, ferrik oksit, titanyum dioksit, G da, Ilaç, ve Kozmetik (FD&C) boyalar' (FD&C mavi, FD&C yesil, FD&C k'rmlz'l,l FD&C sari,l FD&C lake), ponceau, indigo Ilaç ve Kozmetik (D&C) mavisi, indigotin FD&C mavi, karmoisin indigotin (indigo Karmin), demir oksitler (örnegin, k rmlZl, sari, siyah demir oksit), kinolin sarisi, alev kim 2 81,1karmin, karmoisin, günbatlml sar s'l iveya bunlar n kar smlarl olabilir. Suitable coloring agents, non-staining with them: registered sila, ferric oxide, titanium dioxide, Food, Pharmaceutical, and Cosmetic (FD&C) dyes' (FD&C blue, FD&C green, FD&C red,l FD&C yellow,l FD&C lacquer), ponceau, indigo Pharmaceuticals and Cosmetics (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo Carmine), iron oxides (eg, red, yellow, black iron oxide), quinoline yellow, flame who 2 81,1carmine, karmoisine, sunset yellow s'l or can be a mixture of these.

Uygun çözücüler, bunlarla shitolmamasJkaydS/la etil alkol, 2-propanol veya bunlarIi karsLmlar;olabilir. Suitable solvents, not to be confused with them, are ethyl alcohol, 2-propanol or these mixtures; may be.

Mevcut bulusun bir uygulamasima göre, birinci formulasyonu ve ikinci formulasyonu içeren bahsedilen farmasötik kompozisyon; a) toplam kompozisyonda - ag rlüstça %30.0-80.0 direkt trombin inhibitörü serbest bazmi, veya söz konusu inhibitörün farmasötik aç dan kabul edilebilir tuzlar nl,I polimorflarnu solvatlar nl; hidratlarln l veya esterlerini; - aglrl kça %5.0-50.0 seyreltici; - ag Frlkça %1 .0-30.0 baglayßî - agFrl'Rça %0.1-3.0 glidant; - agrrlkça %1 .O-15.0 dagIE: - agtrlkça %0.1-5.0 lubrikan içeren birinci formulasyon b) toplam kompozisyonda - ag Tlikça %10.0-50.0 organik asit pelletleri veya kaplTizole) organik asit pelletleri veya organik asit içeren toz karsmn içeren ikinci formulasyon içermektedir. According to one embodiment of the present invention, comprising the first formulation and the second formulation said pharmaceutical composition; a) in the total composition - 30.0-80.0% direct thrombin inhibitor free base on weight, or the aforementioned pharmaceutically acceptable salts of the inhibitor nl, I polymorphs solvates nl; hydrates l or its esters; - 5.0%-50.0% diluent by weight; - network 1% .0-30.0 in Persian - agFrl'Rca 0.1-3.0% glidant; - 1% by weight .O-15.0 dagIE: - first formulation containing 0.1-5.0% lubricant by weight b) in the total composition - 10.0-50.0% organic acid pellets or coated organic acid pellets, or It contains the second formulation containing powder mixture containing organic acid.

Mevcut bulusun bir uygulamastna göre, birinci formulasyonu ve ikinci formulasyonu içeren bahsedilen farmasötik kompozisyon; a) toplam kompozisyonda - ag rllkça %30.0-80.0 direkt trombin inhibitörü serbest bazln veya söz konusu inhibitörün farmasötik aç dan kabul edilebilir tuzlarîni,i polimorflar'ni,i solvatlar.nl,i hidratlarlnî l veya esterlerini; - ag Elliça %10.0-50.0 seyreltici; - ag Lrlkça %10.0-30.0 baglaytctu - aglrl kça %0.5-3.0 glidant; - aglrlkça %1 .0-15.0 dag tc; - ag Trlkça %0.1-5.0 lubrikan içeren birinci formulasyon b) toplam kompozisyonda - ag Ilmça %10.0-50.0 organik asit pelletleri veya kapljizole) organik asit pelletleri veya organik asit içeren toz kar'Slm içeren ikinci formulasyon içermektedir. According to one embodiment of the present invention, comprising the first formulation and the second formulation said pharmaceutical composition; a) in the total composition - 30.0-80.0% by weight direct thrombin inhibitor free base or pharmaceutically acceptable salts, polymorphs, solvates, hydrates, of inhibitor or its esters; - ag Elliça 10.0-50.0% diluent; - the network was connecting 10.0-30.0% by weight - 0.5-3.0% glidant by weight; - 1% .0-15.0% by weight mountain tc; - ag First formulation containing 0.1-5.0% lubricants b) in the total composition - ag Ilmça 10.0-50.0% organic acid pellets or capljisoled) organic acid pellets or It contains a second formulation containing powder snow containing organic acid.

Mevcut bulusun bir uygulamaSlna göre, birinci formulasyonu ve ikinci formulasyonu içeren bahsedilen farmasötik kompozisyon; a) toplam kompozisyonda - ag Ilikça %10.0-50.0 organik asit pelletleri veya kapljizole) organik asit pelletleri veya organik asit içeren toz kar'SLm içeren birinci formulasyon b) toplam kompozisyonda - ag rllkça %30.0-80.0 direkt trombin inhibitörü serbest bazln veya söz konusu inhibitörün farmasötik açdan kabul edilebilir tuzlarnil polimorflar'hF,` solvatlar'hF,` hidratlarmî veya esterlerini; - ag Lrlkça %5.0-50.0 seyreltici; - aglrl kça %0.1-3.0 glidant; - ag Frlkça %0.1-5.0 lubrikan içeren ikinci formulasyon içermektedir. According to one embodiment of the present invention, comprising the first formulation and the second formulation said pharmaceutical composition; a) in the total composition - ag 10.0-50.0% organic acid pellets or coated organic acid pellets, or First formulation containing powder snow containing organic acid b) in the total composition - 30.0-80.0% by weight direct thrombin inhibitor free base or pharmaceutically acceptable salts of the inhibitor, nyl polymorphs hF, `solvates' hF, `hydrates' or its esters; - 50.0%-50.0% diluent w/w; - 0.1-3.0% glidant by weight; - The ag contains a second formulation containing 0.1-5.0% lubricant.

Mevcut bulusun bir uygulamasßa göre, birinci formulasyonu ve ikinci formulasyonu içeren bahsedilen farmasötik kompozisyon; a) toplam kompozisyonda - ag Tlikça %10.0-50.0 organik asit pelletleri veya kaplTizole) organik asit pelletleri veya organik asit içeren toz karSWn içeren birinci formulasyon b) toplam kompozisyonda - ag rllkça %30.0-80.0 direkt trombin inhibitörü serbest bazln' `veya söz konusu inhibitörün farmasötik aç dan kabul edilebilir tuzlar nl,I polimorflar ni, solvatlar'nl,` hidratlarln l veya esterlerini; - aglrl kça %10.0-50.0 seyreltici; - ag Ilkça %0.5-3.0 glidant; - agîrlltça %1 .0-15.0 dagIE: - agtrlckça %0.1-5.0 lubrikan içeren ikinci formulasyon içermektedir. According to one embodiment of the present invention, comprising the first formulation and the second formulation said pharmaceutical composition; a) in the total composition - 10.0-50.0% organic acid pellets or coated organic acid pellets, or First formulation containing powdered snow containing organic acid b) in the total composition - 30.0-80.0% by weight direct thrombin inhibitor free base or the said pharmaceutically acceptable salts of inhibitor nl, I polymorphs, solvates, hydrates l or its esters; - 10.0-50.0% diluent by weight; - ag 0.5-3.0% glidant first; - 1% by weight .0-15.0 dagIE: - Contains a second formulation containing 0.1-5.0% lubricant by weight.

Mevcut bulusun bir uygulamaslna göre, birinci formulasyonu ve ikinci formulasyonu içeren bahsedilen farmasötik kompozisyon; a) toplam kompozisyonda - ag Ilikça %30.0-80.0 dabigatran eteksilat serbest bazmüveya dabigatran eteksilatîn farmasötik açidan kabul edilebilir tuzlarlnl,l polimorflarlnl, solvatlar'nl,l hidratlarmi' veya esterlerini; - aglrl kça %5.0-50.0 mikrokristalin selüloz; - aglrl kça %1 .0-30.0 hidroksipropil metil selüloz; - aglrl kça %0.1-3.0 kolloidal silikon dioksit; - ag Frlkça %1 .O-15.0 kroskarmelloz sodyum; - ag Trikça %0.1-5.0 magnezyum stearat içeren birinci formulasyon b) toplam kompozisyonda - agrlkça %10.0-50.0 sitrik asit veya tartarik asit pelletleri veya kapli (izole) sitrik asit veya tartarik asit pelletleri veya sitrik asit veya tartarik asit içeren toz kar's m içeren ikinci formulasyon içermektedir. According to one embodiment of the present invention, comprising the first formulation and the second formulation said pharmaceutical composition; a) in the total composition - ag Warmly 30.0-80.0% dabigatran etexilate free base or dabigatran etexilate pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters; - 5.0%-50.0% by weight microcrystalline cellulose; - 1% .0-30.0% hydroxypropyl methyl cellulose by weight; - 0.1-3.0% by weight colloidal silicon dioxide; - ag 1% .O-15.0 croscarmellose sodium; - First formulation containing 0.1-5.0% magnesium stearate in ag Tricka b) in the total composition - 10.0-50.0% by weight of citric acid or tartaric acid pellets or coated (isolated) citric acid or a second containing tartaric acid pellets or a powder mixture containing citric acid or tartaric acid. contains formulation.

Mevcut bulusun bir uygulamasmia göre, birinci formulasyonu ve ikinci formulasyonu içeren bahsedilen farmasötik kompozisyon; a) toplam kompozisyonda - ag rI kça %30.0-80.0 dabigatran eteksilat serbest bazlnl Neya dabigatran eteksilat n farmasötik açFdan kabul edilebilir tuzlarmm polimorflarmii solvatlarnm hidratlarTliî veya esterlerini; - ag Ütlkça %10.0-50.0 mikrokristalin selüloz; - agtrlkça %10-30.0 hidroksipropil metil selüloz; - aglrl kça %0.5-3.0 kolloidal silikon dioksit; - ag Frlkça %1 .0-15.0 kroskarmelloz sodyum; - ag Wikça %0.1-5.0 magnezyum stearat içeren birinci formulasyon b) toplam kompozisyonda - ag r'l kça %10.0-50.0 sitrik asit veya tartarik asit pelletleri veya kapll (izole) sitrik asit veya tartarik asit pelletleri veya sitrik asit veya tartarik asit içeren toz karis m içeren ikinci formulasyon içermektedir. According to one embodiment of the present invention, comprising the first formulation and the second formulation said pharmaceutical composition; a) in the total composition - 30.0-80.0% by weight dabigatran etexilate free base Ne or dabigatran etexilate n polymorphs of pharmaceutically acceptable salts, hydrates of solvates, or esters; - ag 10.0-50.0% microcrystalline cellulose; - 10-30.0% by weight hydroxypropyl methyl cellulose; - 0.5-3.0% by weight colloidal silicon dioxide; - ag 1% .0-15.0% croscarmellose sodium; - First formulation containing 0.1-5.0% magnesium stearate b) in the total composition - 10.0-50.0% by weight citric acid or tartaric acid pellets or coated (isolated) citric acid or a second containing tartaric acid pellets or a powder mixture containing citric acid or tartaric acid contains formulation.

Mevcut bulusun bir uygulamaslna göre, birinci formulasyonu ve ikinci formulasyonu içeren bahsedilen farmasötik kompozisyon; a) toplam kompozisyonda - agrlkça %10.0-50.0 sitrik asit veya tartarik asit pelletleri veya kaplu(izole) sitrik asit veya tartarik asit pelletleri veya sitrik asit veya tartarik asit içeren toz karisim içeren birinci formulasyon b) toplam kompozisyonda - ag Ilkça %30.0-80.0 dabigatran eteksilat serbest baztîiüveya dabigatran eteksilatIi farmasötik açmlan kabul edilebilir tuzlarmm polimorflarmil: solvatlarîm, hidratlarn: veya esterlerini; - aglrl kça %5.0-50.0 mikrokristalin selüloz; - aglrl kça %1 .O-30.0 hidroksipropil metil selüloz; - aglrl kça %0.1-3.0 kolloidal silikon dioksit; - aglrl kça %1 .0-15.0 kroskarmelloz sodyum; - ag Frlkça %0.1-5.0 magnezyum stearat içeren ikinci formulasyon içermektedir. According to one embodiment of the present invention, comprising the first formulation and the second formulation said pharmaceutical composition; a) in the total composition - 10.0-50.0% by weight of citric acid or tartaric acid pellets or coated (isolated) citric acid or first containing tartaric acid pellets or a powder mixture containing citric acid or tartaric acid. formulation b) in the total composition - ag 30.0-80.0% dabigatran etexilate free base or dabigatran etexilate polymorphs of pharmaceutically acceptable salts: solvates, hydrates: or esters; - 5.0%-50.0% by weight microcrystalline cellulose; - 1% by weight .O-30.0 hydroxypropyl methyl cellulose; - 0.1-3.0% by weight colloidal silicon dioxide; - 1% .0-15.0 croscarmellose sodium by weight; - Contains a second formulation containing 0.1-5.0% magnesium stearate ag.

Mevcut bulusun bir uygulamasma göre, birinci formulasyonu ve ikinci formulasyonu içeren bahsedilen farmasötik kompozisyon; a) toplam kompozisyonda - ag leça %10.0-50.0 sitrik asit veya tartarik asit pelletleri veya kaplWizole) sitrik asit veya tartarik asit pelletleri veya sitrik asit veya tartarik asit içeren toz karlSlm içeren birinci formulasyon b) toplam kompozisyonda - ag rl kça %30.0-80.0 dabigatran eteksilat serbest bazlnl Neya dabigatran eteksilat n farmasötik açidan kabul edilebilir tuzlarlnl,l polimorflarmil, solvatlar nl,l hidratlar ni veya esterlerini; - ag TI'Rça %10.0-50.0 mikrokristalin selüloz; - ag Ütlkça %10-30.0 hidroksipropil metil selüloz; - agtrlkça %0.5-3.0 kolloidal silikon dioksit; - aglrl kça %1 .0-15.0 kroskarmelloz sodyum; - ag Frlkça %0.1-5.0 magnezyum stearat içeren ikinci formulasyon içermektedir. According to one embodiment of the present invention, comprising the first formulation and the second formulation said pharmaceutical composition; a) in the total composition - ag leca 10.0-50.0% citric acid or tartaric acid pellets or kaplWizole) citric acid or first containing tartaric acid pellets or a powder mixture containing citric acid or tartaric acid. formulation b) in the total composition - 30.0-80.0% by weight dabigatran etexilate free base Ne or dabigatran etexilate pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters; - ag TI'Rca 10.0-50.0% microcrystalline cellulose; - ag 10-30.0% hydroxypropyl methyl cellulose; - 0.5-3.0% by weight of colloidal silicon dioxide; - 1% .0-15.0 croscarmellose sodium by weight; - Contains a second formulation containing 0.1-5.0% magnesium stearate ag.

Mevcut bulusun bir uygulamasîta göre, söz konusu bulusun farmasötik kompozisyonlarÇ asag daki adimlardan olusan bir proses ile haz rlanabilir: a. Birinci formülasyon mini tabletler veya granüller veya pelletler veya toz veya boncuklar veya kapsüller veya bunlar n karls mIar formunda hazirlanlr; b. Ikinci formülasyon mini tabletler veya granüller veya pelletler veya toz veya boncuklar veya kapsüller veya bunlar n karis mIar formunda hazirlanlr; c. Ikinci formülasyon ikinci kapsülün içine doldurulur ve; d. Ikinci kapsül birinci kapsülün içine yerlestirilir ve ard Indan birinci formülasyon birinci kapsüle Farmasötik Kompozisyon Dabigatran Organik Dabigatran Organik Dabigatran Organik Dabigatran Organik Dabigatran Organik Dabigatran Organik Kati Dozaj Formu Pelletler o Granüller 0 Birinci Mini tabletler 9 Klm" Boncuklar + Kapsüller i› Pelletler o 1› o o o o Granüller o 1› o o o ç Ikinci Mini tabletler & + + 0 4 + Kapsül Boncuklar o o o o 0 + Kapsüller o 1› o o ç i› Farmasötik Kompozisyon Dabigatran Organik Dabigatrari Organik Dabigatran Organik Dabigitran Organik Dabigatran Organik Dabigatran Organik Eteksilat Asit Eteksilat Asit Eteksilat Asit Ehksilat Asit Eteksilat Asit Eteksilat Asit Kati Dozaj Formu Granüller s Birinci Mini tabletler 0 Klm' Boncuklar › Kapsüller o Pelletler «› 9 ç i, o o Granüller o 1› + + 0 s Ikinci Mini ubletler o 1› + 6 i i› Kapsüller o 1› + 0 ç i› Tablo 1 ve Tablo 2'ye göre, 1'den 6'ya kadar numaralandltlan örneklerin tümü, dabigatran eteksilat ve bir organik asit içermektedir. Bu tablolar tüm alternatif farmasötik formülasyonlarl t göstermektedir. baslangç materyalinden her biri neredeyse aynîboyutta ve sekilde partiküllerden olusan granüler bir ürün hazIIama prosesi anlamîta gelmektedir. Burada kullanman sekliyle Mevcut bulusun kompozisyonlarü, bir tozun, bir baglayEEt/e bir çözücü ile karßtmtldtgwe daha sonra granül haline getirildigi yas granülasyon prosesleri, çift bask:(slugging) yöntemi veya sütlStTma ve direkt baskîgibi kuru granülasyon prosesleri veya bir tozun @yla eriyen baglayßm ile kar strldgl lve slyla granülasyona tabi tutuldugu ergitme yöntemiyle granülasyon prosesleri kullanilarak hazrlanabilir. Bu granülasyon prosesleri, planet kar st ri Cllar veya vidal, l karstmclar gibi makinelerle kullanilan karîstîrmalî granülasyon (agitating granulation), Henschel karStIEilar ve süper karîstIîcIar gibi makinelerle kullanilan yüksek hza sahip karstmcl'arla granülasyon (high shear granulation), silindirik, döner granülatör, vidalJ ekstrüzyon granülatörü ve pellet ögütme granülatörü gibi makinelerle kullan lan ekstrüzyon granülasyonu yöntemi gibi çesitli granülasyon prosesleri ile veya kazanda granülasyon (tumbling-granulation) yöntemi, akskan yatak yöntemiyle granülasyon, sik'stlrma yöntemiyle granülasyon, ezme (crushing) granülasyonu yöntemi ve püskürterek kurutma yöntemi ile granülasyon gibi diger prosesler ile kombine edilebilir. Yukarda belirtilen granülasyon prosesleri tek bas na kullan labilir ve kullanimlar nda herhangi bir slnlnlama yoktur. According to one embodiment of the present invention, the pharmaceutical compositions of the present invention It can be prepared by a process consisting of the following steps: a. The first formulation is mini-tablets or granules or pellets or powder or beads or prepared in the form of capsules or a mixture of them; b. Second formulation mini tablets or granules or pellets or powder or beads or prepared in the form of capsules or a mixture thereof; c. The second formulation is filled into the second capsule and; D. The second capsule is placed inside the first capsule and then the first formulation is inserted into the first capsule. pharmaceutical Composition Dabigatran Organic Dabigatran Organic Dabigatran Organic Dabigatran Organic Dabigatran Organic Dabigatran Organic Strict Dosage Form pellets it Granules 0 First Mini-tablets 9 Klm" Beads + Capsules i› Pellets o 1› o o o o Granules o 1› o o o ç Second Mini tablets & + + 0 4 + Capsule Beads o o o o 0 + Capsules o 1› o o ç i› pharmaceutical Composition Dabigatran Organic Dabigatrari Organic Dabigatran Organic Dabigitran Organic Dabigatran Organic Dabigatran Organic Ethexylate Acid Ethexylate Acid Ethexylate Acid Ethoxylate Acid Ethexylate Acid Ethexylate Acid Strict Dosage Form Granules p First Mini-tablets 0 Klm' Beads › capsules it Pellets «› 9 çi, o o Granules o 1› + + 0 s Second Mini ublets o 1› + 6 i i› Capsules o 1› + 0 ç i› According to Table 1 and Table 2, all of the examples numbered 1 to 6 were dabigatran. It contains etexilate and an organic acid. These tables contain all alternative pharmaceutical formulations. shows. the starting material, each consisting of particles of almost the same size and shape. means a granular product preparation process. How you use it here The compositions of the present invention are more complex when a powder is mixed with a binder and a solvent. wet granulation processes, where it is then granulated, double pressing (slugging) method or dry granulation processes such as milking and direct printing, or melting bonding with a powder granulation by melting method in which snow strldgl and silica are granulated with can be prepared using processes. These granulation processes, planetary mixer Cllar or screw, l agitating granulation used with machines such as mixers, High-speed mixers used with machines such as Henschel mixers and super mixers granulation (high shear granulation), cylindrical, rotary granulator, screw extrusion used with machines such as extrusion granulator and pellet milling granulator granulation with various granulation processes such as granulation method or granulation in the boiler (tumbling-granulation) method, granulation by accent bed method, squeezing method granulation, crushing granulation method and spray drying method. It can be combined with other processes such as granulation. granulation mentioned above processes can be used alone and there are no restrictions on their use.

Partiküller granül haline getirildikten sonra, arzu edilen partikül boyutunu elde etmek için ögütülebilirler. Granüllerin ögütülmesi için uygun proseslere örnekler, çekiçle ögütme, bilyalî ögütme, sîiýenerjili ögütme, merdaneli ögütme, kesmeli ögütme veya teknikte bilinen diger anlamna gelmektedir. “Küçük partikül” çapü uzunlugu, yüksekligi ve genisligi en fazla 10 mm olan (örn., en fazla 2, 3, 4, 5, 6, 7, 8 veya 9 mm) partikül anlamTia gelmektedir. sferonizasyon prosesi ile üretilen boncuk, boncukçuk (beadlets), küresel partiküller, sferoid veya benzerlerine karsilik gelmektedir. daha büyük tabletler halinde daha fazla sikîstiîlan, 4 mm'ye esit veya 4 mm'den daha küçük bir çapa sahip küçük tabletler anlamma gelmektedir. Söz konusu mini tabletlerin kaIIJILgJS mm'ye esit veya 3 mm'den daha küçüktür. Mini tabletler, kaplama islemini kolaylastran yuvarlak bir biçime ve pürüzsüz bir yüzeye sahiptirler. After the particles are granulated, to obtain the desired particle size they can be grinded. Examples of suitable processes for grinding granules, hammer milling, ball milling grinding, sii-energy grinding, roller grinding, shear grinding or any other known in the art it means. “Small particle” diameter, length, height and width not more than 10 mm (eg, no more than 2, 3, 4, 5, 6, 7, 8 or 9 mm). Beads, beads, spherical particles, spheroids produced by the spheronization process or similar. more compressed into larger tablets, less than or equal to 4 mm means small tablets of one diameter. KaIIJILgJS of the mini tablets in question It is equal to or less than 3 mm. Mini tablets, which facilitate the coating process They have a round shape and a smooth surface.

Mevcut bulusun bir diger uygulamasi söz konusu farmasötik kompozisyonu hazmama prosesi ile ilgili olup; bahsedilen birinci veya ikinci formülasyonun hazlîlama prosesi asag îdaki ad Inlarj içermektedir: a. Dabigatran eteksilat serbest baz veya dabigatran eteksilat n farmasötik açdan kabul edilebilir tuzlarl,l polimorflar ,l solvatlar ,` hidratlar veya esterleri ve en az bir farmasötik açdan kabul edilebilir eksipiyan kar stln llr; b. Ad m (a)'da elde edilen kars m granül haline getirilir; 0. Adim (b)'de elde edilen granüller kurutulur veya sogutulur; d.Istege baglîolarak, admn (c)'de elde edilen granüllere en az bir farmasötik açîlan kabul edilebilir eksipiyan eklenir ve karßtîrilE. e. Karsm birinci veya ikinci kapsüle doldurulur. Another application of the present invention is the process of digesting the pharmaceutical composition in question. is related to; the preparation process of said first or second formulation is called Inlarj includes: a. Dabigatran etexilate free base or dabigatran etexilate is pharmaceutically acceptable soluble salts, polymorphs, solvates, hydrates or esters, and at least one pharmaceutical acceptable excipient balance; b. The mixture obtained in step (a) is granulated; 0. The granules obtained in step (b) are dried or cooled; d.Optionally accept at least one pharmaceutical opening into the granules obtained in step (c) excipient is added and mixed. to. Karsm is filled into the first or second capsule.

Mevcut bulusun bir diger uygulamas , söz konusu farmasötik kompozisyonu hazirlama prosesi ile ilgili olup; bahsedilen birinci veya ikinci formülasyonun haziîlama prosesi asag daki ad Tnlar'î içermektedir: a. Organik asit ve istege bagluolarak en az bir farmasötik aç'dan kabul edilebilir eksipiyan kar stm lln; b. Ad m (a)'da elde edilen kar slm, organik asit granülleri elde etmek üzere granül haline getirilir veya adim (a)'da elde edilen kar s m, organik asit pelletleri elde etmek üzere ekstrüzyona veya sferonizasyona tabi tutulur; c. Istege baglîolarak organik asit granülleri veya pelletleri izolasyon çözeltisi ile kaplan T; d. AdEn (b)'de veya ad In (c)'de elde edilen organik asit granülleri veya pelletleri birinci kapsüle veya ikinci kapsüle doldurulur. Another application of the present invention is the process of preparing said pharmaceutical composition. is related to; the preparation process of said first or second formulation is named below. includes: a. Organic acid and optionally at least one pharmaceutically acceptable excipient snow stm lln; b. The snow slurry obtained in step m (a) is granulated to obtain organic acid granules. or the mixture obtained in step (a) can be extruded or extruded to obtain organic acid pellets. subjected to spheronization; c. Optionally, organic acid granules or pellets are coated with isolation solution T; D. The organic acid granules or pellets obtained in AdEn (b) or ad In (c) are transferred to the first capsule. or filled into the second capsule.

Mevcut bulusun bir diger uygulamasîsöz konusu farmasötik kompozisyonu hazmama prosesi ile ilgili olup; bahsedilen proses asagmlaki adWhlarîçermektedir: a. Birinci formulasyon hazîlanî; i. Direkt trombin inhibitörü serbest baz' Veya söz konusu inhibitörün farmasötik aç'dan kabul edilebilir tuzlar, polimorflar`,l solvatlarl,l hidratlari lveya esterleri, seyreltici, baglaylc, glidant, dag t cl kar st n lin; ii. Ad m (i)'de elde edilen karlSlm granüle edilir; iii. Adm (ii)'de elde edilen granüller kurutulur; iv. Istege baglH olarak, adm1(iii)'te elde edilen granüllere Iubrikan ilave edilir ve karîstmm; b. Ikinci formulasyon hazirlanin; i. Organik asit ve tercihen en az bir farmasötik açidan kabul edilebilir eksipiyan kar's'tin Im; ii. Ad m1(i)'de elde edilen karSTn, organik asit pelletleri elde etmek üzere ekstrüzyona veya sferonizasyona tabi tutulur; iii. Istege baglîolarak, organik asit pelletleri bir izolasyon çözeltisi ile kaplan I; 0. Ikinci formülasyon ikinci kapsülün içine doldurulur ve; d. Ikinci kapsül birinci kapsülün içine yerlestirilir ve ard ndan birinci formülasyon birinci kapsüle Mevcut bulusun bir diger uygulamas , söz konusu farmasötik kompozisyonu hazirlama prosesi ile ilgili olup; bahsedilen proses asagîdaki adWhIarýiçermektedir: a. Birinci formulasyon hazîlanî; i. Organik asit ve tercihen en az bir farmasötik aç'dan kabul edilebilir eksipiyan kar stiri lin; ii. Adim(i)'de elde edilen karis m, organik asit pelletleri elde etmek üzere ekstrüzyona veya sferonizasyona tabi tutulur; iii. Istege bagl `olarak, organik asit pelletleri bir izolasyon çözeltisi ile kaplan r; b. Ikinci formulasyon haz'rlanin; i. Direkt trombin inhibitörü serbest bez veya söz konusu inhibitörün farmasötik aç dan kabul edilebilir tuzlar, polimorflar`,i solvatlari,i hidratlari iveya esterleri, seyreltici, baglayici, glidant, dag t ci kar st n lin; ii. AdTn (i)'de elde edilen karTsFm granüle edilir; iii. Adîn (ii)'de elde edilen granüller kurutulur; iv. Istege baglü olarak, adin(iii)'te elde edilen granüllere Iubrikan ilave edilir ve karstmlin; c. Ikinci formülasyon ikinci kapsülün içine doldurulur ve; d. Ikinci kapsül birinci kapsülün içine yerlestirilir ve ard hdan birinci formülasyon birinci kapsüle Mevcut bulusun bir diger uygulamas , söz konusu farmasötik kompozisyonu hazirlama prosesi ile ilgili olup; bahsedilen proses asagidaki adimlar içermektedir: a. Birinci formulasyon haz rlan r; i. Dabigatran eteksilat serbest baz veya dabigatran eteksilat ni farmasötik aç olan kabul edilebilir tuzlar ,i polimorflar ,i solvatlari,i hidratlar . veya esterleri, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum kariStîilFr; ii. AdIn (i)ide elde edilen karüsîn su ile granüle edilir; iii. Adm (ii)'de elde edilen granüller kurutulur; iv. Istege bagl 'olarak, adim(iii)'te elde edilen granüllere magnezyum stearat ilave edilir ve kar's't ri lir; b. Ikinci formulasyon hazTlaniI; i. Sitrik asit veya tartarik asit, mikrokristalin selüloz ve hidroksipropil selüloz içeren izopropil alkol çözeltisi ile karstîm; ii. Adim(i)'de elde edilen kar's m, sitrik asit pelletleri veya tartarik asit pelletleri elde etmek üzere ekstrüzyona veya sferonizasyona tabi tutulur; iii. Istege bagl ,olarak, sitrik asit pelletleri veya tartarik asit pelletleri bir izolasyon çözeltisi ile kaplan r; 0. Ikinci formülasyon ikinci kapsülün içine doldurulur ve; d. Ikinci kapsül birinci kapsülün içine yerlestirilir ve ard ndan birinci formülasyon birinci kapsüle Mevcut bulusun bir diger uygulamas , söz konusu farmasötik kompozisyonu hazirlama prosesi ile ilgili olup; bahsedilen proses asagFdaki adiîhlarîçermektedir: a. Birinci formulasyon haz rlan r; i. Sitrik asit veya tartarik asit, mikrokristalin selüloz ve hidroksipropil selüloz içeren izopropil alkol çözeltisi ile kar Stlrllir; ii. Ad:m(i)'de elde edilen kars m, sitrik asit pelletleri veya tartarik asit pelletleri elde etmek üzere ekstrüzyona veya sferonizasyona tabi tutulur; iii. Istege baglîolarak, sitrik asit pelletleri veya tartarik asit pelletleri bir izolasyon çözeltisi ile kaplan T; b. Ikinci formulasyon hazîlanm; i. Dabigatran eteksilat serbest baz;Veya dabigatran eteksilatn farmasötik aç'dan kabul edilebilir tuzlar.,l polimorflar,l solvatlarl,1 hidratlar S veya esterleri, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum karFStTiW; ii. Adîn (i)'de elde edilen karFsEn su ile granüle edilir; iii. AdIn (ii)'de elde edilen granüller kurutulur; iv. Istege bagl 'olarak, adrm(iii)'te elde edilen granüllere magnezyum stearat ilave edilir ve kar st n Ilr; 0. Ikinci formülasyon ikinci kapsülün içine doldurulur ve; d. Ikinci kapsül birinci kapsülün içine yerlestirilir ve ard ndan birinci formülasyon birinci kapsüle Mevcut bulusun bir diger uygulamas:söz konusu farmasötik kompozisyonu hazEIama prosesi ile ilgili olup; bahsedilen birinci veya ikinci formülasyonun hazirlama prosesi asagdaki ad'mlau içermektedir: a. Dabigatran eteksilat serbest baz 'veya dabigatran eteksilat'n farmasötik aç dan kabul edilebilir tuzlarm polimorflarîi solvatlarî hidratlarýveya esterleri ve en az bir farmasötik açdan kabul edilebilir eksipiyan elenir ve karîstmilî; b. Toz karîsîm süglstîma veya çift baskjslugging) islemine tabi tutulur; c. 8 k'stirllan toz elenir veya çift baskldan geçirilen briket tabletler (slug'lar) ögütülür ve elenir; d. Istege bagliolarak karSÜtna en az bir farmasötik açIlan kabul edilebilir eksipiyan eklenir ve 1-2 dakika daha karstmîlîr. e. Toz kar s m mini tabletler halinde bas Ilr. f. Mini tabletler birinci veya ikinci kapsüle doldurulur. Another application of the present invention is the process of digesting the pharmaceutical composition in question. is related to; the mentioned process includes the following names: a. The first formulation is in preparation; I. Direct thrombin inhibitor free base or pharmaceutical derivative of said inhibitor acceptable salts, polymorphs, solvates, hydrates or esters, diluent, binder, glidant, dag t cl kar st n lin; ii. The mixture obtained in step (i) is granulated; iii. The granules obtained in step (ii) are dried; iv. Optionally, Iubrikan is added to the granules obtained in adm1(iii) and karistm; b. Prepare the second formulation; I. Organic acid and preferably at least one pharmaceutically acceptable excipient Kar's'tin Im; ii. KarSTn obtained in Ad m1(i) is extruded to obtain organic acid pellets. or spheronized; iii. Optionally, the organic acid pellets are coated with an isolation solution I; 0. The second formulation is filled into the second capsule and; D. The second capsule is placed inside the first capsule and then the first formulation is inserted into the first capsule. Another application of the present invention is the process of preparing said pharmaceutical composition. is related to; said process includes the following names: a. The first formulation is in preparation; I. Organic acid and preferably at least one pharmaceutically acceptable excipient snow stir lin; ii. The mixture obtained in step(i) is extruded to obtain organic acid pellets. or spheronized; iii. Optionally, the organic acid pellets are covered with an isolation solution; b. Prepare the second formulation; I. A direct thrombin inhibitor is free gland or a pharmaceutically active inhibitor of the said inhibitor. acceptable salts, polymorphs, solvates, hydrates or esters of i, diluent, binder, glidant, dist t ci kar st n lin; ii. The cardTsFm obtained in AdTn (i) is granulated; iii. The granules obtained in Adin (ii) are dried; iv. Optionally, Iubrikan is added to the granules obtained in adin(iii) and karstmlin; c. The second formulation is filled into the second capsule and; D. The second capsule is placed inside the first capsule and then the first formulation is inserted into the first capsule. Another application of the present invention is the process of preparing said pharmaceutical composition. is related to; The mentioned process includes the following steps: a. The first formulation is prepared; I. Dabigatran etexilate free base or dabigatran etexilate is considered pharmaceutically hungry soluble salts, polymorphs, solvates, hydrates. or its esters, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide, and croscarmellose sodium mixtures; ii. The carucine obtained in AdIn (i) is granulated with water; iii. The granules obtained in step (ii) are dried; iv. Optionally, magnesium stearate is added to the granules obtained in step(iii). and kar's't ri li; b. The second formulation was prepared; I. Containing citric acid or tartaric acid, microcrystalline cellulose and hydroxypropyl cellulose mixed with isopropyl alcohol solution; ii. The snow obtained in step(i) is obtained as citric acid pellets or tartaric acid pellets. extruded or spheronized to iii. Optionally, citric acid pellets or tartaric acid pellets can be used for isolation. r covered with solution; 0. The second formulation is filled into the second capsule and; D. The second capsule is placed inside the first capsule and then the first formulation is inserted into the first capsule. Another application of the present invention is the process of preparing said pharmaceutical composition. is related to; the mentioned process includes the following: a. The first formulation is prepared; I. Containing citric acid or tartaric acid, microcrystalline cellulose and hydroxypropyl cellulose Snow Stabilized with isopropyl alcohol solution; ii. Name: The mixture obtained in m(i) yields citric acid pellets or tartaric acid pellets. extruded or spheronized to iii. Optionally, citric acid pellets or tartaric acid pellets can be used as an isolation. coated with solution T; b. I prepared the second formulation; I. Dabigatran etexilate free base; or dabigatran etexilate pharmaceutically acceptable salts, 1 polymorphs, 1 solvates, 1 hydrates S or their esters, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium carFStTiW; ii. The snow obtained in Adin (i) is granulated with water; iii. The granules obtained in AdIn (ii) are dried; iv. Optionally, magnesium stearate is added to the granules obtained in adrm(iii). and snow st n Ilr; 0. The second formulation is filled into the second capsule and; D. The second capsule is placed inside the first capsule and then the first formulation is inserted into the first capsule. Another application of the present invention is the process of preparing said pharmaceutical composition. is related to; the preparation process of said first or second formulation is ad'mlau below includes: a. Dabigatran etexilate free base or dabigatran etexilate is pharmaceutically acceptable. polymorphs, solvates, hydrates or esters of soluble salts and at least one pharmaceutical acceptable excipient is eliminated and karistmili; b. The powder mixture is subjected to the process of sublimation or double baskjslugging; c. 8 k'stirllan powder is sieved or double-pressed briquette tablets (slugs) are ground and sieved; D. Optionally add at least one pharmaceutically acceptable excipient to the milk, and It is mixed for 1-2 more minutes. to. The powder mix is pressed into mini tablets. f. Mini tablets are filled into the first or second capsule.

Mevcut bulusun bir diger uygulamas , söz konusu farmasötik kompozisyonu hazirlama prosesi ile ilgili olup; bahsedilen birinci veya ikinci formülasyonun hazirlama prosesi asag daki ad mlar l içermektedir: a. Organik asit ve istege bagllîolarak en az bir farmasötik açîlan kabul edilebilir eksipiyan elenir ve karîstmlî; b. Toz karsm suitstro'dan geçirilir veya slugging islemine tabi tutulur; 0. 8 k sttnllan toz elenir veya briket tabletler (slug'lar) ögütülür ve elenir; d. Istege baglîolarak karsmia en az bir farmasötik açdan kabul edilebilir eksipiyan eklenir ve 1-2 dakika daha karstm Ilr. e. Toz kar s m mini tabletler halinde bas lir. f. Mini tabletler birinci veya ikinci kapsüle doldurulur. Another application of the present invention is the process of preparing said pharmaceutical composition. is related to; the preparation process of said first or second formulation follows the steps l includes: a. Organic acid and optionally at least one pharmaceutically acceptable excipient eliminated and confused; b. The powder mix is passed through the suitstro or slugging; 0.8 k solid powder is sieved or briquette tablets (slugs) are ground and sieved; D. Optionally, at least one pharmaceutically acceptable excipient is added to the mix and I stirred for another 1-2 minutes. to. The powder mix is pressed as mini-tablets. f. Mini tablets are filled into the first or second capsule.

Bir uygulamaya göre, organik asit pelletleri veya organik asit granülleri, izolasyon çözeltisi ile kaplan r. According to one embodiment, organic acid pellets or organic acid granules are mixed with isolation solution. tiger r.

Bir uygulamaya göre, izolasyon çözeltisi, polimerik veya polimerik olmayan farmasötik olarak kabul edilebilir bir bilesenden veya bunlarn herhangi bir kombinasyonundan olusmaktad I. According to one embodiment, the isolation solution may be polymeric or non-polymeric pharmaceutical. an acceptable component or any combination thereof.

Bir uygulamaya göre, kapsül materyali, hidroksipropil metil selüloz (HPMC) veya alkali ile muamele edilmis jelatin veya asit ile muamele edilmis jelatin veya kimyasal olarak modifiye edilmis jelatindir. In one embodiment, the capsule material is hydroxypropyl methyl cellulose (HPMC) or with alkali. treated gelatin or acid-treated gelatin or chemically modified is gelatin.

Bir uygulamaya göre, kapsül materyali aerîza, agar, nisasta, aljinik asit, guar zamkÇ plastiklestirici ve bunlar'n karsm'n' içerebilir. According to one embodiment, the capsule material is aeriza, agar, starch, alginic acid, guar gum. may contain plasticizer and mixtures thereof.

HPMC bazl kapsüllerin jelatin bazl: kapsüllere göre dissolüsyon h zln geciktirici etkisi vardln. HPMC-based capsules have a retarding effect on the dissolution rate compared to gelatin-based: capsules.

Asit kullan lan farmasötik kompozisyonda, jelatin bazll kapsüller, HPMC bazl kapsüllere göre daha fazla tercih edilir. In the pharmaceutical composition using acid, gelatin-based capsules are compared to HPMC-based capsules. more preferred.

Bir uygulamaya göre, organik asit pelletleri veya kapl:organik asit pelletleri veya organik asit içeren toz karsmjçeren kapsül, jelatinden veya HPMC'den, tercihen jelatinden olusmaktadtn. According to one embodiment, organic acid pellets or coated: organic acid pellets or organic acid The capsule containing the powder mixture consists of gelatin or HPMC, preferably gelatin.

Bir uygulamaya göre, sitrik asit pelletleri veya kapi` sitrik asit pelletleri veya sitrik asit içeren toz kar slm, içeren kapsül, jelatinden veya HPMC'den, tercihen jelatinden olusmaktadlr. According to one embodiment, citric acid pellets or capped citric acid pellets or powder containing citric acid The countermeasure, the capsule containing, is composed of gelatin or HPMC, preferably gelatin.

Bir uygulamaya göre, tartarik asit pelletleri veya kaplîtartarik asit pelletleri veya tartarik asit içeren toz karÇsmLiçeren kapsül, jelatinden veya HPMC'den, tercihen jelatinden olusmaktadirn. According to one embodiment, tartaric acid pellets or captivetartaric acid pellets or tartaric acid The capsule containing powder mixture containing gelatin or HPMC, preferably gelatin.

Bir uygulamaya göre, dabigatran eteksilat serbest baz nl`veya dabigatran eteksilat'n farmasötik aç olan kabul edilebilir tuzlarlnil,` polimorflarm',` solvatlarnî,` hidratlar'm'yeya esterlerini içeren kapsül jelatinden veya HPMClden olusmaktad ri. In one embodiment, dabigatran etexilate free base nl or dabigatran etexilate pharmaceutically acceptable salts, 'polymorphs', 'solvates', 'hydrates' or The capsule containing its esters consists of gelatin or HPMC.

Birinci Kapsül Içerigi Ag'rrlirkça % Dabigatran eteksilat serbest baz* veya dabigatran eteksilatîfi farmasötik açKlan kabul edilebilir tuzlar, polimorflarl,. solvatlar, 30.0 - 80.0 hidratlar veya esterleri Mikrokristalin selüloz 5.0 - 50.0 Hidroksipropil metil selüloz 1.0 - 30.0 Kolloidal Silikon dioksit 0.1 - 3.0 Kroskarmelloz sodyum 1.0 - 15.0 Magnezyum stearat 0.1 - 5.0 Ikinci Kapsül Içerigi Kapl' 1(Izole) Organik Asit Pelletleri / Organik Asit Pelletleri / Organik Asit Içeren Toz 10.0 - 50.0 TOPLAM 100.0 Organik Asit Pelletlerinin Haz'rilan sl: Organik asit ve mikrokristalin selüloz kar Stîrlllr ve bu kar s m, yas bir kütle elde etmek için hidroksipropil selüloz içeren izopropil alkol çözeltisine eklenir. Söz konusu yas kütle, pellet elde etmek üzere ekstrüzyona, sferonizasyona tabi tutulur, kurutulur ve elenir. First Capsule Content Weight % Dabigatran etexilate free base* or dabigatran astringent pharmaceutical openKlan acceptable salts, polymorphs, . solvates, 30.0 - 80.0 hydrates or esters Microcrystalline cellulose 5.0 - 50.0 Hydroxypropyl methyl cellulose 1.0 - 30.0 Colloidal Silicon dioxide 0.1 - 3.0 Croscarmellose sodium 1.0 - 15.0 Magnesium stearate 0.1 - 5.0 Second Capsule Content Kapl' 1(Isolated) Organic Acid Pellets / Organic Acid Pellets / Powder Containing Organic Acids 10.0 - 50.0 TOTAL 100.0 Preparation of Organic Acid Pellets: Organic acid and microcrystalline cellulose snow are stabilized and this mixture is used to obtain a smooth mass. It is added to the isopropyl alcohol solution containing hydroxypropyl cellulose. The aforementioned age mass is obtained from pellets. It is extruded, spheronized, dried and sieved.

Izole Organik Asit Pelletlerinin (Kapli Organik Asit Pelletleri) Haz rlan s : Izolasyon çözeltisinin hazîlanSE Formül 1: Saf suya HPMC ve sukroz ilave edilir ve karlstlnllr. Elde edilen karsma talk eklenir ve karstmlm. Preparation of Isolated Organic Acid Pellets (Coated Organic Acid Pellets): Preparation of the isolation solution Formula 1: HPMC and sucrose are added to pure water and mixed. Talc is added to the resulting mixture and i am confused.

Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve karstLrUir. Elde edilen karLSLma talk eklenir ve kar stln lln. Formula 2: HPMC and triethyl citrate are added to pure water and mixed. Talc is added to the resulting mixture and snow style lln.

Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde karFstITlî Elde edilen karßima talk ve PEG 6000 ilave edilir ve homojenizatörde karlst r'llr. Formula 3: HPMC is added to the pure water and mixed in the homogenizer. The resulting mixture of talc and PEG 6000 is added and mixed in the homogenizer.

Organik asit pelletleri, Formül 1 ila 3 aras ndan seçilen izolasyon çözeltisi ile kaplanlr. The organic acid pellets are coated with the isolation solution selected from Formulas 1 to 3.

Organik Asit Içeren Toz Karis m nun Hazlrlan si l Organik asit, spreyle kurutulmus Iaktoz, kolloidal silikon dioksit ve prejelatinize nisasta elenir ve karstîlî. Magnezyum stearat eklenir ve 1-2 dakika daha karStTliî. Üretim yöntemi 1: Dabigatran Eteksilat Granüllerinin Hazmlanls7` Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karstîliît Bu karsrn su ile granül haline getirilir. Preparation of Powder Mixture Containing Organic Acids Organic acid, spray-dried lactose, colloidal silicon dioxide and pregelatinized starch are sieved and karstîl. Magnesium stearate is added and mixed for another 1-2 minutes. Production method 1: Hazmlanls7` of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium is sieved and the karstiliite mixture is granulated with water.

Granüller 50°C'de kurutulur ve elenir. Kurutulmus granüllere magnezyum stearat ilave edilir ve kar stm lln. The granules are dried at 50°C and sieved. Magnesium stearate is added to the dried granules and kar stm lln.

Iç Içe Yerlestirilmis Kapsüllerin Haz nlanls Kapi organik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz kar s m l ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve dabigatran eteksilat granülleri, birinci kapsüle doldurulur. Üretim yöntemi 2: Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karlst'r llri. Toz kar s m suyla granül haline getirilir ve 50°C'Iik fWrtida kurutulur. Magnezyum stearat eklenir ve 1-2 dakika daha kar'StWi'lT. Toz Iç Içe Yerlestirilmis Kapsüllerin Haz rlanls Kapl organik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz kar s m 1 ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve mini tabletler formundaki dabigatran eteksilat birinci kapsüle doldurulur. Üretim yöntemi 3: Dabigatran Eteksilat Granüllerinin Hazlrlani Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum kar'strlm. Magnezyum stearatn bir kSml karls ma eklenir ve karstnlm. KarLSLm, silindirler araszskstlrma yöntemi (roller compaction) ile kompres edilir. Preparation of Nested Capsules Kapi organic acid pellets or organic acid pellets or powder mix containing organic acid filled into the second capsule. The second capsule is placed inside the first capsule and dabigatran etexilate granules are filled into the first capsule. Production method 2: Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. Powder mixture is granulated with water and dried at 50°C. Magnesium stearate is added and mixed for 1-2 more minutes. Dust Preparation of Nested Capsules Coated organic acid pellets or organic acid pellets or powder mix containing organic acid 1 filled into the second capsule. The second capsule is placed inside the first capsule and the mini-tablets dabigatran etexilate in the form of is filled into the first capsule. Production method 3: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium mixture. One part of magnesium stearate is added to the mixture and i am confused. KarLSLm is compressed by roller compaction method.

Kompres edilen karls m (granüller) elenir. Kalan magnezyum elenen granüllere eklenir ve kar stnlln. The compressed mixture (granules) is sieved. The remaining magnesium is added to the sieved granules and profit stnlln.

Iç Içe Yerlestirilmis Kapsüllerin Hazîlangý Kapl organik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz kar s m' ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve dabigatran eteksilat granülleri, birinci kapsüle doldurulur. Preparation of Nested Capsules Coated organic acid pellets or organic acid pellets or powder mix containing organic acid. filled into the second capsule. The second capsule is placed inside the first capsule and dabigatran etexilate granules are filled into the first capsule.

Birinci Kapsül Içerigi Ag rl kça % Kapl i(Izole) Organik Asit Pelletleri / Organik Asit Pelletleri / Organik Asit Içeren Toz 10.0 - 50.0 Ikinci Kapsül Içerigi Dabigatran eteksilat serbest baz veya dabigatran eteksilat n farmasötik açidan kabul edilebilir tuzlar; poiimorriarr,, solvatlarj. 30'0 ' 800 hidratlar ,veya esterleri Mikrokristalin selüloz 5.0 - 50.0 Hidroksipropil metil selüloz 1.0 - 30.0 Kolloidal Silikon dioksit 0.1 - 3.0 Kroskarmelloz sodyum 1.0 - 15.0 Magnezyum stearat 0.1 - 5.0 TOPLAM 100.0 Organik Asit Pelletlerinin Hazrlan si: Organik asit ve mikrokristalin selüloz kar strllir ve bu kar S m, yas bir kütle elde etmek için hidroksipropil selüloz içeren izopropil alkol çözeltisine eklenir. Söz konusu yas kütle, pellet elde etmek üzere ekstrüzyona, sferonizasyona tabi tutulur, kurutulur ve elenir. First Capsule Content Weight % Coated (Isolated) Organic Acid Pellets / Organic Acid Pellets / Powder Containing Organic Acids 10.0 - 50.0 Second Capsule Content Dabigatran etexilate free base or dabigatran etexilate from a pharmaceutical point of view acceptable salts; poiimorriarr, solvatlarj. 30'0' 800 hydrates, or esters Microcrystalline cellulose 5.0 - 50.0 Hydroxypropyl methyl cellulose 1.0 - 30.0 Colloidal Silicon dioxide 0.1 - 3.0 Croscarmellose sodium 1.0 - 15.0 Magnesium stearate 0.1 - 5.0 TOTAL 100.0 Preparation of Organic Acid Pellets: Organic acid and a mixture of microcrystalline cellulose are mixed and this mixture is S m, to obtain a smooth mass. It is added to the isopropyl alcohol solution containing hydroxypropyl cellulose. The aforementioned age mass is obtained from pellets. It is extruded, spheronized, dried and sieved.

Izole Organik Asit Pelletlerinin (Kapli Organik Asit Pelletleri) Haz rlans : Izolasyon çözeltisinin haz rlan si: Formül 1: Saf suya HPMC ve sukroz ilave edilir ve karlstnllr. Elde edilen kar's ma talk eklenir ve karstnlln. Preparation of Isolated Organic Acid Pellets (Coated Organic Acid Pellets): Preparation of the isolation solution: Formula 1: HPMC and sucrose are added to pure water and mixed. Talc is added to the resulting snow and karstnlln.

Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve kar stlrlllr. Elde edilen karlslma talk eklenir ve kar st ni llri. Formula 2: HPMC and triethyl citrate are added to the pure water and mixed. Talc is added to the resulting mixture and snow st ni llri.

Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde karlstîlîr. Elde edilen karlSîna talk ve PEG 6000 ilave edilir ve homojenizatörde karßtfrilü. Formula 3: HPMC is added to the pure water and mixed in the homogenizer. The obtained karlSîna talc and PEG 6000 is added and mixed in the homogenizer.

Organik asit pelletleri, Formül 1 ila 3 aras ndan seçilen izolasyon çözeltisi ile kaplanlr. The organic acid pellets are coated with the isolation solution selected from Formulas 1 to 3.

Organik Asit Içeren Toz Karsmîiîi HazWIanST Organik asit, spreyle kurutulmus Iaktoz, kolloidal silikon dioksit ve prejelatinize nisasta elenir ve kar'st r` Ilr. Magnezyum stearat eklenir ve 1-2 dakika daha kar'st'r llr. Üretim yöntemi 1: Dabigatran Eteksilat Granüllerinin Hazlrlan s Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karstîflm Bu karsTn su ile granül haline getirilir. Powder Mixture Containing Organic Acids HazWIanST Organic acid, spray-dried lactose, colloidal silicon dioxide and pregelatinized starch are sieved ve kar'st r` Ilr. Magnesium stearate is added and mixed for another 1-2 minutes. Production method 1: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water.

Granüller 50°C'de kurutulur ve elenir. Kurutulmus granüllere magnezyum stearat ilave edilir ve karst »ni Jin. The granules are dried at 50°C and sieved. Magnesium stearate is added to the dried granules and karst »ni Jin.

Iç Içe Yerlestirilmis Kapsüllerin Haz'nlanls Dabigatran eteksilat granülleri, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kapljorganik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz karîsîn, birinci kapsül içine doldurulur. Üretim yöntemi 2: Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karlstrllr. Toz kar s m suyla granül haline getirilir ve 50°C'Iik fîmda kurutulur. Magnezyum stearat eklenir ve 1-2 dakika daha karistFrj'l'lr. Toz karsLm mini tabletler seklinde baslllr. Pleasure of Nested Capsules Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule. are placed and coated with organic acid pellets or organic acid pellets or containing organic acid. powdered powder is filled into the first capsule. Production method 2: Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. Powder mixture is granulated with water and dried at 50°C. Magnesium stearate is added and mixed for 1-2 more minutes. Dust The mixture is printed as mini tablets.

Iç Içe Yerlestirilmis Kapsüllerin Haz'nlanls ` Mini tabletler formundaki dabigatran eteksilat, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kaplzOrganik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz kar s m, birinci kapsül içine doldurulur. Üretim yöntemi 3: Dabigatran Eteksilat Granüllerinin HazWIanSI Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum karstrlm. Magnezyum stearatn bir kismi .karls ma eklenir ve kar strllln. KarlSlm, silindirler aras' `skstlrma yöntemi (roller compaction) ile kompres edilir. Pleasure of Nested Capsules ` Dabigatran etexilate in the form of mini-tablets is filled into the second capsule. second capsule, first placed in the capsule and coated with organic acid pellets or organic acid pellets or organic powder mixture containing acid is filled into the first capsule. Production method 3: Pleasure of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium mixed. Some of the magnesium stearate is added to the mixture and snow strlln. KarlSlm is compressed by roller compaction method between rollers.

Kompres edilen karls m (granüller) elenir. Kalan magnezyum elenen granüllere eklenir ve karstîTFr. The compressed mixture (granules) is sieved. The remaining magnesium is added to the sieved granules and karstîTFr.

Iç Içe Yerlestirilmis Kapsüllerin Hazîîlanrs* Dabigatran eteksilat granülleri, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kapl `organik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz kar's m, birinci kapsül içine doldurulur. Preparations of Nested Capsules* Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule. placed and coated with organic acid pellets or organic acid pellets or containing organic acid powder snow's m is filled into the first capsule.

Birinci Kapsül Içerigi Ag nl kça % Dabigatran eteksilat serbest baz veya dabigatran eteksilatn farmasötik açidan kabul edilebilir tuzlar ji polimorflarU solvatlarj 30.0 - 80.0 hidratlarzveya esterleri Mikrokristalin selüloz 5.0 - 50.0 Hidroksipropil metil selüloz 1.0 - 30.0 Kolloidal Silikon dioksit 0.1 - 3.0 Kroskarmelloz sodyum 1.0 - 15.0 Magnezyum stearat 0.1 - 5.0 Ikinci Kapsül Içerigi Kapl i(IzoIe) Sitrik Asit Pelletleri / Sitrik Asit Pelletleri / Sitrik Asit Içeren Toz Karsm TOPLAM 100.0 .0 - 50.0 Sitrik Asit Pelletlerinin Haz'rlan s.:l Sitrik asit ve mikrokristalin selüloz kar strlm ve bu karis m, yas bir kütle elde etmek için hidroksipropil selüloz içeren izopropil alkol çözeltisine eklenir. Söz konusu yas kütle, pellet elde etmek üzere ekstrüzyona, sferonizasyona tabi tutulur, kurutulur ve elenir. First Capsule Content Weight % Dabigatran etexilate free base or dabigatran etexilate from a pharmaceutical perspective acceptable salts j polymorphsU solvates 30.0 - 80.0 hydrates or esters Microcrystalline cellulose 5.0 - 50.0 Hydroxypropyl methyl cellulose 1.0 - 30.0 Colloidal Silicon dioxide 0.1 - 3.0 Croscarmellose sodium 1.0 - 15.0 Magnesium stearate 0.1 - 5.0 Second Capsule Content Coated(Isolated) Citric Acid Pellets / Citric Acid Pellets / Powder Mixture Containing Citric Acid TOTAL 100.0 .0 - 50.0 Preparation of Citric Acid Pellets: l Citric acid and microcrystalline cellulose were mixed and this mixture was used to obtain a smooth mass. It is added to the isopropyl alcohol solution containing hydroxypropyl cellulose. The aforementioned age mass, pellet It is extruded, spheronized, dried and sieved to obtain

Izole Sitrik Asit Pelletlerinin (Kapli Sitrik Asit Pelletleri) Haz rlanis :0 Izolasyon çözeltisinin haz rlan si: Formül 1: Saf suya HPMC ve sukroz ilave edilir ve karßtîw. Elde edilen karSTna talk eklenir ve karîstîlii. Preparation of Isolated Citric Acid Pellets (Coated Citric Acid Pellets) :0 Preparation of the isolation solution: Formula 1: HPMC and sucrose are added to pure water and mixed. Talc is added to the resulting mixture and charisma

Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve karLStt'rilJr. Elde edilen kartsßma talk eklenir ve kar stri Im. Formula 2: HPMC and triethyl citrate are added to the pure water and mixed. Talc is added to the resulting mixture and kar stri Im.

Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde karßtîTFr. Elde edilen karßîna talk ve PEG 6000 ilave edilir ve homojenizatörde karFstIîlI. Formula 3: HPMC is added to pure water and mixed in the homogenizer. The resulting talc and PEG 6000 is added and mixed in the homogenizer.

Sitrik asit pelletleri, Formül 1 ila 3 arasindan seçilen izolasyon çözeltisi ile kaplan r. Citric acid pellets are coated with the isolation solution selected from Formulas 1 to 3.

Sitrik Asit Içeren Toz Kar sm n n Hazirlan s Sitrik asit, spreyle kurutulmus Iaktoz, kolloidal silikon dioksit ve prejelatinize nisasta elenir ve karstîlm. Magnezyum stearat eklenir ve 1-2 dakika daha karîstrgliîi. Üretim yöntemi 1: Dabigatran Eteksilat Granüllerinin Hazirlanis Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit Granüller 50°C'de kurutulur ve elenir. Kurutulmus granüllere magnezyum stearat ilave edilir ve kar'stîi'im. Preparation of Powder Mixture Containing Citric Acid Citric acid, spray-dried lactose, colloidal silicon dioxide and pregelatinized starch are sieved and karstîlm. Magnesium stearate is added and mixed for another 1-2 minutes. Production method 1: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide The granules are dried at 50°C and sieved. Magnesium stearate is added to the dried granules and im kar'stîi.

Iç Içe Yerlestirilmis Kapsüllerin Haz nlanls Kapll sitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz kar slm ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve dabigatran eteksilat granülleri, birinci kapsüle doldurulur. Üretim yöntemi 2: Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karlst'r llr`. Toz kar s'm suyla granül haline getirilir ve 50°C'Iik f'rlmda kurutulur. Magnezyum stearat eklenir ve 1-2 dakika daha kar stlrllr. Toz karstm mini tabletler seklinde bastllr'. Preparation of Nested Capsules Coated citric acid pellets or citric acid pellets or powder mix containing citric acid is placed in the second capsule. is filled. The second capsule is placed inside the first capsule and the dabigatran etexilate granules, filled into the first capsule. Production method 2: Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium is sieved and karlst'r llr`. Powder snow is granulated with water and dried in an oven at 50°C. Magnesium stearate is added and stirred for another 1-2 minutes. Dust mixed in the form of mini-tablets'.

Iç Içe Yerlestirilmis Kapsüllerin Haz nlanls Kapll sitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz kar slm ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve mini tabletler formundaki dabigatran eteksilat birinci kapsüle doldurulur. Üretim yöntemi 3: Dabigatran Eteksilat Granüllerinin Hazirlanis7` Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum karStTTlTi. Magnezyum stearatn bir ksmrkarßîna eklenir ve karstmm KarSEn, silindirler araszisICstIima yöntemi (roller compaction) ile kompres edilir. Preparation of Nested Capsules Coated citric acid pellets or citric acid pellets or powder mix containing citric acid is placed in the second capsule. is filled. The second capsule is placed inside the first capsule and is in the form of mini-tablets. dabigatran etexilate is filled into the first capsule. Production method 3: Preparation of Dabigatran Ethexylate Granules7` Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium mixture. A portion of magnesium stearate is added to the mixture and karstmm KarSEn is compressed with the roller compaction method (roller compaction) between the rollers.

Kompres edilen karls m (granüller) elenir. Kalan magnezyum elenen granüllere eklenir ve kar st nlln. The compressed mixture (granules) is sieved. The remaining magnesium is added to the sieved granules and snow st nlln.

Iç Içe Yerlestirilmis Kapsüllerin Haz nlanls Kapl. sitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz kar Slm. ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve dabigatran eteksilat granülleri, birinci kapsüle doldurulur. Preparation of Nested Capsules cap. citric acid pellets or citric acid pellets or powder snow containing citric acid Slm. to the second capsule is filled. The second capsule is placed inside the first capsule and the dabigatran etexilate granules, filled into the first capsule.

Birinci Kapsül Içerigi Ag nl kça % Kapl i(IzoIe) Sitrik Asit Pelletleri / Sitrik Asit Pelletleri / Sitrik Asit Içeren Toz Kar s m Ikinci Kapsül Içerigi Dabigatran eteksilat serbest baz veya .0 - 80.0 dabigatran eteksilatn farmasötik açidan kabul edilebilir tuzlar', polimorflarl,i solvatlar', hidratlar veya esterleri Mikrokristalin selüloz 5.0 - 50.0 Hidroksipropil metil selüloz 1.0 - 30.0 Kolloidal Silikon dioksit 0.1 - 3.0 Kroskarmelloz sodyum 1.0 - 15.0 Magnezyum stearat 0.1 - 5.0 TOPLAM Sitrik Asit Pelletlerinin Haz'rlan sLzl Sitrik asit ve mikrokristalin selüloz karstrlm ve bu karls m, yas bir kütle elde etmek için hidroksipropil selüloz içeren izopropil alkol çözeltisine eklenir. Söz konusu yas kütle, pellet elde etmek üzere ekstrüzyona, sferonizasyona tabi tutulur, kurutulur ve elenir. First Capsule Content Weight % Coated(Isolated) Citric Acid Pellets / Citric Acid Pellets / Powder Mixture Containing Citric Acid Second Capsule Content Dabigatran etexilate free base or .0 - 80.0 dabigatran etexilate from a pharmaceutical perspective acceptable salts', polymorphs, solvates', hydrates or esters Microcrystalline cellulose 5.0 - 50.0 Hydroxypropyl methyl cellulose 1.0 - 30.0 Colloidal Silicon dioxide 0.1 - 3.0 Croscarmellose sodium 1.0 - 15.0 Magnesium stearate 0.1 - 5.0 TOTAL Preparation of Citric Acid Pellets Citric acid and microcrystalline cellulose were mixed and this mixture was used to obtain a flat mass. It is added to the isopropyl alcohol solution containing hydroxypropyl cellulose. The aforementioned age mass, pellet It is extruded, spheronized, dried and sieved to obtain

Izole Sitrik Asit Pelletlerinin (Kapll Sitrik Asit Pelletleri) Haz rlan's :. Preparation of Isolated Citric Acid Pellets (Coated Citric Acid Pellets) :.

Izolasyon çözeltisinin hazirlanisl: Formül 1: Saf suya HPMC ve sukroz ilave edilir ve karstrillr. Elde edilen karsma talk eklenir ve karstîîm. Preparation of the isolation solution: Formula 1: HPMC and sucrose are added to pure water and mixed. Talc is added to the resulting mixture and karstîm

Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve karStWmT. Elde edilen karFsTna talk eklenir ve kar st n lln. Formula 2: HPMC and triethyl citrate are added to the pure water and karStWmT. Talc is added to the resulting mixture and karst n lln.

Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde karlst r llr. Elde edilen kar s ma talk ve PEG 6000 ilave edilir ve homojenizatörde karlst r llr. Formula 3: HPMC is added to pure water and mixed in the homogenizer. The resulting mixture of talc and PEG 6000 is added and mixed in the homogenizer.

Sitrik asit pelletleri, Formül 1 ila 3 arasmdan seçilen izolasyon çözeltisi ile kaplanr. Citric acid pellets are coated with the isolation solution selected from Formulas 1 to 3.

Sitrik Asit Içeren Toz Kar sm n n Hazirlan s Sitrik asit, spreyle kurutulmus laktoz, kolloidal silikon dioksit ve prejelatinize nisasta elenir ve kar st'ri lln. Magnezyum stearat eklenir ve 1-2 dakika daha karist r llri. Üretim yöntemi 1: Dabigatran Eteksilat Granüllerinin Hazlîflan'S *' Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve kar'st r lln. Bu karis'm su ile granül haline getirilir. Preparation of Powder Mixture Containing Citric Acid Citric acid, spray-dried lactose, colloidal silicon dioxide and pregelatinized starch are sieved and kar st'ri lln. Magnesium stearate is added and mixed for another 1-2 minutes. Production method 1: Hazlîflan'S *' of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water.

Granüller 50°C'de kurutulur ve elenir. Kurutulmus granüllere magnezyum stearat ilave edilir ve kar st ni llri. The granules are dried at 50°C and sieved. Magnesium stearate is added to the dried granules and snow st ni llri.

Iç Içe Yerlestirilmis Kapsüllerin Hazîtlanrs* Dabigatran eteksilat granülleri, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kapli sitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz kar s m, birinci kapsül içine doldurulur. Üretim yöntemi 2: Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karlst r Ilr. Toz kar s m suyla granül haline getirilir ve 50°C'Iik firlnda kurutulur. Magnezyum stearat eklenir ve 1-2 dakika daha kar stlr Ilr. Toz kar slm mini tabletler seklinde baslllr. Prepared Nested Capsules* Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule. placed and coated citric acid pellets or citric acid pellets or powder mixture containing citric acid, is filled into the first capsule. Production method 2: Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. Powder mixture is granulated with water and dried in an oven at 50°C. Magnesium stearate is added and mixed for another 1-2 minutes. Dust They are printed in the form of anti-slip mini tablets.

Iç Içe Yerlestirilmis Kapsüllerin Hazîtlanîs* Mini tabletler formundaki dabigatran eteksilat, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kapl,:sitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz kar s m, birinci kapsül içine doldurulur. Üretim yöntemi 3: Dabigatran Eteksilat Granüllerinin Hazmlans: Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum karstrlln. Magnezyum stearatn bir ksml karls ma eklenir ve kar st n` lln. Karisim, silindirler aras 5 k stlrma yöntemi (roller compaction) ile kompres edilir. Preparation of Nested Capsules* Dabigatran etexilate in the form of mini-tablets is filled into the second capsule. second capsule, first placed in the capsule and coated: citric acid pellets or citric acid pellets or citric acid The powder mixture containing the powder is filled into the first capsule. Production method 3: Ingestion of Dabigatran Ethexylate Granules: Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium mixture. A portion of magnesium stearate is added to the mixture and kar st n` lln. The mixture is compressed between the rollers with the 5 k compression method (roller compaction).

Kompres edilenkar slm (granüller) elenir. Kalan magnezyum elenen granüllere eklenir ve kar st ni lln. The compressed snow slime (granules) is sieved. The remaining magnesium is added to the sieved granules and karst ni lln.

Iç Içe Yerlestirilmis Kapsüllerin Hazîtlanîs: Dabigatran eteksilat granülleri, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kapli sitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz kar s m, birinci kapsül içine doldurulur. Preparation of Nested Capsules: Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule. placed and coated citric acid pellets or citric acid pellets or powder mixture containing citric acid, is filled into the first capsule.

Yukarda 3 ve 4 için verilen örneklerde bulusun bir baska uygulamasîia göre, kapIEsitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz karrsîn yerine kapljtartarik asit pelletleri veya tartarik asit pelletleri veya tartarik asit içeren toz kar slm koyulabilir. According to another embodiment of the invention in the examples given for 3 and 4 above, capIEcitric acid pellets or citric acid pellets or coated tartaric acid instead of powdered carcinogen containing citric acid pellets or tartaric acid pellets or powder mix containing tartaric acid can be added.

Birinci Kapsül Içerigi Ag rl kça % Dabigatran eteksilat serbest baz veya dabigatran eteksilat n farmasötik açidan kabul edilebilir tuzlar, polimorflari,` solvatlar, 30.0 _ 80'0 hidratlar veya esterleri Mikrokristalin selüloz 10.0 - 50.0 Hidroksipropil metil selüloz 10.0 - 30.0 Kolloidal Silikon dioksit 0.5 - 3.0 Kroskarmelloz sodyum 1.0 - 15.0 Magnezyum stearat 0.1 - 5.0 Ikinci Kapsül Içerigi Kapl i(IzoIe) Organik Asit Pelletleri / Organik Asit Pelletleri / Organik Asit Içeren Toz 10.0 - 50.0 TOPLAM 100.0 Organik Asit Pelletlerinin Haz rlan si: Organik asit ve mikrokristalin selüloz kar stîrllr ve bu kar s m, yas bir kütle elde etmek için hidroksipropil selüloz içeren izopropil alkol çözeltisine eklenir. Söz konusu yas kütle, pellet elde etmek üzere ekstrüzyona, sferonizasyona tabi tutulur, kurutulur ve elenir. First Capsule Content Weight % Dabigatran etexilate free base or dabigatran etexilate from a pharmaceutical point of view acceptable salts, polymorphs, solvates, 30.0 _ 80'0 hydrates or esters Microcrystalline cellulose 10.0 - 50.0 Hydroxypropyl methyl cellulose 10.0 - 30.0 Colloidal Silicon dioxide 0.5 - 3.0 Croscarmellose sodium 1.0 - 15.0 Magnesium stearate 0.1 - 5.0 Second Capsule Content Coated(Isolated) Organic Acid Pellets / Organic Acid Pellets / Powder Containing Organic Acids 10.0 - 50.0 TOTAL 100.0 Preparation of Organic Acid Pellets: Organic acid and microcrystalline cellulose are mixed together and this mixture is used to obtain a flat mass. It is added to the isopropyl alcohol solution containing hydroxypropyl cellulose. The aforementioned age mass is obtained from pellets. It is extruded, spheronized, dried and sieved.

Izole Organik Asit Pelletlerinin (Kapli Organik Asit Pelletleri) Haz rlan s : Izolasyon çözeltisinin haz rlan si: Formül 1: Saf suya HPMC ve sukroz ilave edilir ve kar'stinrllr. Elde edilen kariS'ma talk eklenir ve Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve kar st rilir. Elde edilen kar s'ma talk eklenir ve kar st r lin. Preparation of Isolated Organic Acid Pellets (Coated Organic Acid Pellets): Preparation of the isolation solution: Formula 1: HPMC and sucrose are added to pure water and mixed. Talc is added to the resulting mixture and Formula 2: HPMC and triethyl citrate are added to pure water and mixed. Talc is added to the resulting snow and kar st r lin.

Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde kar st'r lir. Elde edilen kar sSma talk ve PEG 6000 ilave edilir ve homojenizatörde karist r lir. Formula 3: HPMC is added to the pure water and the mixture is mixed in the homogenizer. The resulting snow sSma talc and PEG 6000 is added and mixed in the homogenizer.

Organik asit pelletleri, Formül 1 ila 3 arasTidan seçilen izolasyon çözeltisi ile kaplan r. The organic acid pellets are coated with the isolation solution selected from Formulas 1 to 3.

Organik Asit Içeren Toz Kar sm nin Hazlrlan s l Organik asit, spreyle kurutulmus laktoz, kolloidal silikon dioksit ve prejelatinize nisasta elenir ve karst rllri. Magnezyum stearat eklenir ve 1-2 dakika daha karstrillrj. Üretim yöntemi 1: Dabigatran Eteksilat Granüllerinin Hazirlanis Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit Granüller 50°C'de kurutulur ve elenir. Kurutulmus granüllere magnezyum stearat ilave edilir ve karstnlln. Preparation of Powder Mixture Containing Organic Acid The organic acid, spray-dried lactose, colloidal silicon dioxide and pregelatinized starch are sieved. and karst rlri. Magnesium stearate is added and mixed for another 1-2 minutes. Production method 1: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide The granules are dried at 50°C and sieved. Magnesium stearate is added to the dried granules and karstnlln.

Iç Içe Yerlestirilmis Kapsüllerin Haz rlanls Kapl organik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz kar s m l ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve dabigatran eteksilat granülleri, birinci kapsüle doldurulur. Üretim yöntemi 2: Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karßtrliî. Toz karsm suyla granül haline getirilir ve 50°C'Iik ffmida kurutulur. Magnezyum stearat eklenir ve 1-2 dakika daha karstFrTlT. Toz karSEn mini tabletler seklinde basmî. Preparation of Nested Capsules Coated organic acid pellets or organic acid pellets or powder mix containing organic acid filled into the second capsule. The second capsule is placed inside the first capsule and dabigatran etexilate granules are filled into the first capsule. Production method 2: Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. The powder mixture is granulated with water. and dried in ffmida at 50°C. Magnesium stearate is added and karstFrTlT for another 1-2 minutes. Dust KarSEn printed in the form of mini tablets.

Iç Içe Yerlestirilmis Kapsüllerin Haz nlanls Kapl organik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz kar s m l ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve mini tabletler formundaki dabigatran eteksilat birinci kapsüle doldurulur. Üretim yöntemi 3: Dabigatran Eteksilat Granüllerinin Hazlrnlanis ; Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum kar strlm. Magnezyum stearatn bir k'Sm' karls'ma eklenir ve karStî'I'm. KarFslîn, silindirler aras*'s'kstrrma yöntemi (roller compaction) ile kompres edilir. Preparation of Nested Capsules Coated organic acid pellets or organic acid pellets or powder mix containing organic acid filled into the second capsule. The second capsule is placed inside the first capsule and the mini-tablets dabigatran etexilate in the form of is filled into the first capsule. Production method 3: Preparation of Dabigatran Ethexylate Granules; Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium mixture. One k'Sm' char of magnesium stearate is added and my karStî'I'm. KarFslin is compressed by roller compaction method.

Kompres edilen karLSIn (granüller) elenir. Kalan magnezyum elenen granüllere eklenir ve karîstîîllî. The compressed snow (granules) is sieved. The remaining magnesium is added to the sieved granules and karîstîllî.

Iç Içe Yerlestirilmis Kapsüllerin Haz rlanls Kapl organik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz kar s m l ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve dabigatran eteksilat granülleri, birinci kapsüle doldurulur. Preparation of Nested Capsules Coated organic acid pellets or organic acid pellets or powder mix containing organic acid filled into the second capsule. The second capsule is placed inside the first capsule and dabigatran etexilate granules are filled into the first capsule.

Birinci Kapsül Içerigi Ag nl kça % Kaplî(Izole) Organik Asit Pelletleri / Organik Asit Pelletleri / Organik Asit Içeren Toz 10.0 - 50.0 Ikinci Kapsül Içerigi Dabigatran eteksilat serbest baz veya dabigatran eteksilatn farmasötik açidan kabul edilebilir tuzlar, polimorflarl, solvatlar, 30.0 - 80'0 hidratlar veya esterleri Mikrokristalin selüloz 10.0 - 50.0 Hidroksipropil metil selüloz 10.0 - 30.0 Kolloidal Silikon dioksit 0.5 - 3.0 Kroskarmelloz sodyum 1.0 - 15.0 Magnezyum stearat 0.1 - 5.0 TOPLAM 100.0 Organik Asit Pelletlerinin HazîlanSE Organik asit ve mikrokristalin selüloz karStTW ve bu karST'n, yas bir kütle elde etmek için hidroksipropil selüloz içeren izopropil alkol çözeltisine eklenir. Söz konusu yas kütle, pellet elde etmek üzere ekstrüzyona, sferonizasyona tabi tutulur, kurutulur ve elenir. First Capsule Content Weight % Coated (Isolated) Organic Acid Pellets / Organic Acid Pellets / Powder Containing Organic Acids 10.0 - 50.0 Second Capsule Content Dabigatran etexilate free base or dabigatran etexilate from a pharmaceutical perspective acceptable salts, polymorphs, solvates, 30.0 - 80'0 hydrates or esters Microcrystalline cellulose 10.0 - 50.0 Hydroxypropyl methyl cellulose 10.0 - 30.0 Colloidal Silicon dioxide 0.5 - 3.0 Croscarmellose sodium 1.0 - 15.0 Magnesium stearate 0.1 - 5.0 TOTAL 100.0 Preparation of Organic Acid Pellets Organic acid and microcrystalline cellulose karStTW and this karST were used to obtain a flat mass. It is added to the isopropyl alcohol solution containing hydroxypropyl cellulose. The aforementioned age mass is obtained from pellets. It is extruded, spheronized, dried and sieved.

Izole Organik Asit Pelletlerinin (Kapll Organik Asit Pelletleri) Haz rlan s : Izolasyon çözeltisinin haz rlan sl: Formül 1: Saf suya HPMC ve sukroz ilave edilir ve kar'stnllr. Elde edilen kar's ma talk eklenir ve kar st n lln. Preparation of Isolated Organic Acid Pellets (Coated Organic Acid Pellets): The prepared water of the isolation solution: Formula 1: HPMC and sucrose are added to pure water and mixed. Talc is added to the resulting snow and karst n lln.

Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve kar stlrlllr. Elde edilen karls ma talk eklenir ve kar st nlln. Formula 2: HPMC and triethyl citrate are added to the pure water and mixed. Talc is added to the resulting mixture and snow st nlln.

Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde karlst nllr. Elde edilen karlSima talk ve PEG 6000 ilave edilir ve homojenizatörde karlstrfllr. Formula 3: HPMC is added to the pure water and mixed in the homogenizer. The resulting karlSima talc and PEG 6000 is added and mixed in the homogenizer.

Organik asit pelletleri, Formül 1 ila 3 arasindan seçilen izolasyon çözeltisi ile kaplantr. The organic acid pellets are coated with the isolation solution selected from Formulas 1 to 3.

Organik Asit Içeren Toz Kar Sim n'n Hazlrlan s" l Organik asit, spreyle kurutulmus Iaktoz, kolloidal silikon dioksit ve prejelatinize nisasta elenir ve kar'st r Ilr. Magnezyum stearat eklenir ve 1-2 dakika daha kar'st r Ilr. Üretim yöntemi 1: Dabigatran Eteksilat Granüllerinin Hazlrlan s Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karstTTm. Bu karsmn su ile granül haline getirilir. Preparation of Organic Acid Containing Powder Snow Sim" l Organic acid, spray-dried lactose, colloidal silicon dioxide and pregelatinized starch are sieved ve kar'st r Ilr. Magnesium stearate is added and mixed for another 1-2 minutes. Production method 1: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium is sieved and mixed. This mixture is granulated with water.

Granüller 50°C'de kurutulur ve elenir. Kurutulmus granüllere magnezyum stearat ilave edilir ve karîstjillîrl. The granules are dried at 50°C and sieved. Magnesium stearate is added to the dried granules and karîstjillîrl.

Iç Içe Yerlestirilmis Kapsüllerin Hazsrllanls Dabigatran eteksilat granülleri, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kaplîorganik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz karîsîn, birinci kapsül içine doldurulur. Üretim yöntemi 2: Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karlst r Iir. Toz kar s m suyla granül haline getirilir ve 50°C'Iik flrlrlida kurutulur. Magnezyum stearat eklenir ve 1-2 dakika daha karstlr llr. Toz karsmi mini tabletler seklinde baslllî. Preparation of Nested Capsules Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule. are placed and coated with organic acid pellets or organic acid pellets or containing organic acid. powdered powder is filled into the first capsule. Production method 2: Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. The powder mixture is granulated with water. and dried at 50°C. Magnesium stearate is added and mixed for another 1-2 minutes. Dust mixed in the form of mini tablets.

Iç Içe Yerlestirilmis Kapsüllerin Haztrllants , Mini tabletler formundaki dabigatran eteksilat, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kapll Organik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz karFSTn, birinci kapsül içine doldurulur. Üretim yöntemi 3: Dabigatran Eteksilat Granüllerinin Hazlrlan's ` Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum kar strlln. Magnezyum stearatn bir ksm' karls ma eklenir ve kar st ri lln. Kar Slm, silindirler aras s k st rima yöntemi (roller compaction) ile kompres edilir. Preparations of Nested Capsules, Dabigatran etexilate in the form of mini-tablets is filled into the second capsule. second capsule, first placed in the capsule and coated Organic acid pellets or organic acid pellets or organic powdered carFSTn containing acid is filled into the first capsule. Production method 3: Preparation's of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium snow strlln. A portion of magnesium stearate is added to the mixture and kar st ri lln. Snow Slm is compressed with the method of compaction between the rollers (roller compaction).

Kompres edilen karls rin (granüller) elenir. Kalan magnezyum elenen granüllere eklenir ve karst ri lln. Compressed snow rin (granules) is sieved. The remaining magnesium is added to the sieved granules and karst ri lln.

Iç Içe Yerlestirilmis Kapsüllerin Hazrlanls'; Dabigatran eteksilat granülleri, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kapl jorganik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz kar's m, birinci kapsül içine doldurulur. Preparation of Nested Capsules'; Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule. placed and coated organic acid pellets or organic acid pellets or containing organic acid powder snow's m is filled into the first capsule.

Birinci Kapsül Içerigi Agîîlkça % Dabigatran eteksilat serbest baz veya dabigatran eteksilat n farmasötik açidan kabul edilebilir tuzlar, polimorflari, solvatlar, 30.0 _ 80.0 hidratlar veya esterleri Mikrokristalin selüloz 10.0 - 50.0 Hidroksipropil metil selüloz 10.0 - 30.0 Kolloidal Silikon dioksit 0.5 - 3.0 Kroskarmelloz sodyum 1.0 - 15.0 Magnezyum stearat 0.1 - 5.0 Ikinci Kapsül Içerigi Kapl S(Izole) Sitrik Asit Pelletleri / Sitrik Asit Pelletleri / Sitrik Asit Içeren Toz Karsm 10.0 _ 500 TOPLAM 100.0 Sitrik Asit Pelletlerinin Hazrlan .s;:l Sitrik asit ve mikrokristalin selüloz kar'st'rillr ve bu kars m, yasbir kütle elde etmek için hidroksipropil selüloz içeren izopropil alkol çözeltisine eklenir. Söz konusu yas kütle, pellet elde etmek üzere ekstrüzyona, sferonizasyona tabi tutulur, kurutulur ve elenir. First Capsule Content Weight % Dabigatran etexilate free base or dabigatran etexilate from a pharmaceutical point of view acceptable salts, polymorphs, solvates, 30.0 _ 80.0 hydrates or esters Microcrystalline cellulose 10.0 - 50.0 Hydroxypropyl methyl cellulose 10.0 - 30.0 Colloidal Silicon dioxide 0.5 - 3.0 Croscarmellose sodium 1.0 - 15.0 Magnesium stearate 0.1 - 5.0 Second Capsule Content Kapl S(Isolated) Citric Acid Pellets / Citric Acid Pellets / Powder Mixture Containing Citric Acid 10.0 _ 500 TOTAL 100.0 Preparation of Citric Acid Pellets .s;:l Citric acid and microcrystalline cellulose mixtures and this mixture are used to obtain a flat mass. It is added to the isopropyl alcohol solution containing hydroxypropyl cellulose. The aforementioned age mass is obtained from pellets. It is extruded, spheronized, dried and sieved.

Izole Sitrik Asit Pelletlerinin (Kapll Sitrik Asit Pelletleri) Haz rilan's :î Izolasyon çözeltisinin haz rlan si: Formül 1: Saf suya HPMC ve sukroz ilave edilir ve kar strllr. Elde edilen karsma talk eklenir ve kar st nlln. Preparation of Isolated Citric Acid Pellets (Coated Citric Acid Pellets) :î Preparation of the isolation solution: Formula 1: HPMC and sucrose are added to the pure water and the snow is formed. Talc is added to the resulting mixture and snow st nlln.

Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve kar stlrlllr. Elde edilen karlSlma talk eklenir ve karst ni lln. Formula 2: HPMC and triethyl citrate are added to the pure water and mixed. Talc is added to the resulting mixture and karst ni lln.

Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde karLst'nllr. Elde edilen karLS'ma talk ve PEG 6000 ilave edilir ve homojenizatörde karlstir llr. Formula 3: HPMC is added to the pure water and mixed in the homogenizer. Talc and PEG to the obtained karLS 6000 is added and mixed in the homogenizer.

Sitrik asit pelletleri, Formül 1 ila 3 arasindan seçilen izolasyon çözeltisi ile kaplan'r. Citric acid pellets are coated with the isolation solution selected from Formulas 1 to 3.

Sitrik Asit Içeren Toz Kar,s;mnn Hazlnlans; Sitrik asit, spreyle kurutulmus Iaktoz, kolloidal silikon dioksit ve prejelatinize nisasta elenir ve kar st n` lln. Magnezyum stearat eklenir ve 1-2 dakika daha karist r lln. Üretim yöntemi 1: Dabigatran Eteksilat Granüllerinin Hazmlangý Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karistmln. Bu karisLm su ile granül haline getirilir. Powder Snow Containing Citric Acid, Preparation of Mine; Citric acid, spray-dried lactose, colloidal silicon dioxide and pregelatinized starch are sieved and kar st n` lln. Add magnesium stearate and mix for another 1-2 minutes. Production method 1: Ingestion of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water.

Granüller 50°C'de kurutulur ve elenir. Kurutulmus granüllere magnezyum stearat ilave edilir ve karstîTm. The granules are dried at 50°C and sieved. Magnesium stearate is added to the dried granules and karstîTm.

Iç Içe Yerlestirilmis Kapsüllerin HazîilanlS: Kapl;`sitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz kar'SLmJkinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve dabigatran eteksilat granülleri, birinci kapsüle doldurulur. Üretim yöntemi 2: Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karßtTIlTr. Toz karsrn suyla granül haline getirilir ve 50°C'Iik flrlrlida kurutulur. Magnezyum stearat eklenir ve 1-2 dakika daha karstlrillr. Toz karsmi mini tabletler seklinde basillî. Preparation of Nested Capsules: Covered with 'citric acid pellets or citric acid pellets or powder mixture containing citric acid' into the second capsule is filled. The second capsule is placed inside the first capsule and the dabigatran etexilate granules, filled into the first capsule. Production method 2: Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. The powder mixture is granulated with water. and dried at 50°C. Magnesium stearate is added and mixed for another 1-2 minutes. Dust mixed in the form of mini-tablets.

Iç Içe Yerlestirilmis Kapsüllerin HazîilanlSî Kaplîsitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz karîsmniikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve mini tabletler formundaki dabigatran eteksilat birinci kapsüle doldurulur. Üretim yöntemi 3: Dabigatran Eteksilat Granüllerinin Hazlrlans Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum karistrglli. Magnezyum stearatn bir ksmlî karlS ma eklenir ve karstnlln. KarlSlm, silindirler arassslkstlrma yöntemi (roller compaction) ile kompres edilir. Preparation of Nested Capsules Capped citric acid pellets or citric acid pellets or powder mixture containing citric acid into the second capsule. is filled. The second capsule is placed inside the first capsule and is in the form of mini-tablets. dabigatran etexilate is filled into the first capsule. Production method 3: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium mixed. It is added to a partial mixture of magnesium stearate and karstnlln. KarlSlm is compressed by roller compaction method.

Kompres edilenkarslm (granüller) elenir. Kalan magnezyum elenen granüllere eklenir ve kar st rl lln. The compressed mixture (granules) is sieved. The remaining magnesium is added to the sieved granules and profit st rl lln.

Iç Içe Yerlestirilmis Kapsüllerin Haz rllanls ` Kapl;sitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz karslm ,ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve dabigatran eteksilat granülleri, birinci kapsüle doldurulur. Preparation of Nested Capsules ` Coated; citric acid pellets or citric acid pellets or powder mixture containing citric acid, in a second capsule is filled. The second capsule is placed inside the first capsule and the dabigatran etexilate granules, filled into the first capsule.

Birinci Kapsül Içerigi Ag rl'kça % Kapl Z(Izole) Sitrik Asit Pelletleri / Sitrik Asit Pelletleri / Sitrik Asit Içeren Toz Kar s m 100 _ 50.0 Ikinci Kapsül Içerigi Dabigatran eteksilat serbest baz* veya dabigatran eteksilath farmasötik açldan kabul edilebilir tuzlarî polimorflarT, solvatlarî 30.0 _ 80.0 hidratlar veya esterleri Mikrokristalin selüloz 10.0 - 50.0 Hidroksipropil metil selüloz 10.0 - 30.0 Kolloidal Silikon dioksit 0.5 - 3.0 Kroskarmelloz sodyum 1.0 - 15.0 Magnezyum stearat 0.1 - 5.0 TOPLAM Sitrik Asit Pelletlerinin Hazrlan s :l Sitrik asit ve mikrokristalin selüloz kar st rlln ve bu karls m, yas bir kütle elde etmek için hidroksipropil selüloz içeren izopropil alkol çözeltisine eklenir. Söz konusu yas kütle, pellet elde etmek üzere ekstrüzyona, sferonizasyona tabi tutulur, kurutulur ve elenir. First Capsule Content by Weight % Coated Z(Isolated) Citric Acid Pellets / Citric Acid Pellets / Powder Snow Containing Citric Acid s m 100 _ 50.0 Second Capsule Content Dabigatran etexilate free base* or dabigatran etsilath pharmaceutical acceptable salts polymorphsT, solvates 30.0 _ 80.0 hydrates or esters Microcrystalline cellulose 10.0 - 50.0 Hydroxypropyl methyl cellulose 10.0 - 30.0 Colloidal Silicon dioxide 0.5 - 3.0 Croscarmellose sodium 1.0 - 15.0 Magnesium stearate 0.1 - 5.0 TOTAL Preparation of Citric Acid Pellets :l Citric acid and microcrystalline cellulose are mixed and this mixture is used to obtain a smooth mass. It is added to the isopropyl alcohol solution containing hydroxypropyl cellulose. The aforementioned age mass is obtained from pellets. It is extruded, spheronized, dried and sieved.

Izole Sitrik Asit Pelletlerinin (Kapll Sitrik Asit Pelletleri) Haz nlanis :: Izolasyon çözeltisinin haz rlan si: Formül 1: Saf suya HPMC ve sukroz ilave edilir ve karrstîîllî. Elde edilen karSTna talk eklenir ve karstnlm. Preparation of Isolated Citric Acid Pellets (Coated Citric Acid Pellets) :: Preparation of the isolation solution: Formula 1: HPMC and sucrose are added to pure water and karrstîllî. Talc is added to the resulting mixture and i am confused.

Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve kar stlrlllr. Elde edilen karlSlma talk eklenir ve kar'StTlllTl. Formula 2: HPMC and triethyl citrate are added to the pure water and mixed. Talc is added to the resulting mixture and kar'StTlllTl.

Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde karistnlir. Elde edilen karlSLma talk ve PEG 6000 ilave edilir ve homojenizatörde karlstlr lir. Formula 3: HPMC is added to pure water and mixed in the homogenizer. The resulting mixture of talc and PEG 6000 is added and mixed in the homogenizer.

Sitrik asit pelletleri, Formül 1 ila 3 arasindan seçilen izolasyon çözeltisi ile kaplan r. Citric acid pellets are coated with the isolation solution selected from Formulas 1 to 3.

Sitrik Asit Içeren Toz Kargîmîiî'i Hazmlanýs* Sitrik asit, spreyle kurutulmus Iaktoz, kolloidal silikon dioksit ve prejelatinize nisasta elenir ve karstnlln. Magnezyum stearat eklenir ve 1-2 dakika daha karistlrlln'. Üretim yöntemi 1: Dabigatran Eteksilat Granüllerinin HazFrilan3`, Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve kar'st r lln. Bu karîs'm su ile granül haline getirilir. Ingestion of Powder Kargîmîi Containing Citric Acid* Citric acid, spray-dried lactose, colloidal silicon dioxide and pregelatinized starch are sieved and karstnlln. Magnesium stearate is added and mixed for another 1-2 minutes. Production method 1: HazFrilan3` of Dabigatran Ethexylate Granules, Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This karîs is granulated with water.

Granüller 50°C'de kurutulur ve elenir. Kurutulmus granüllere magnezyum stearat ilave edilir ve kar st nlln. The granules are dried at 50°C and sieved. Magnesium stearate is added to the dried granules and snow st nlln.

Iç Içe Yerlestirilmis Kapsüllerin Haz rilanls Dabigatran eteksilat granülleri, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kaplEsitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz karîsîn, birinci kapsül içine doldurulur. Üretim yöntemi 2: Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve kariStI'JlI. Toz karISIJ'n suyla granül haline getirilir ve 50°C'Iik fîmda kurutulur. Magnezyum stearat eklenir ve 1-2 dakika daha kar'îstîrjî. Toz kar slm mini tabletler seklinde baslliri. Preparation of Nested Capsules Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule. is placed and coated with citric acid pellets or citric acid pellets or powder mixture containing citric acid, is filled into the first capsule. Production method 2: Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. Powder mix is granulated with water. and dried at 50°C. Magnesium stearate is added and mixed for another 1-2 minutes. Dust The snow slide is titled as mini-tablets.

Iç Içe Yerlestirilmis Kapsüllerin Haz nlanls Mini tabletler formundaki dabigatran eteksilat, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kapi :sitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz kariS Tin, birinci kapsül içine doldurulur. Üretim yöntemi 3: Dabigatran Eteksilat Granüllerinin Hazirlanis Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum kar'strlm. Magnezyum stearatn bir kSml karls ma eklenir ve karstnlin. KarLSLm, silindirler aras,s,k,sttrma yöntemi (roller compaction) ile kompres edilir. Preparation of Nested Capsules Dabigatran etexilate in the form of mini-tablets is filled into the second capsule. second capsule, first placed in the capsule and capped: citric acid pellets or citric acid pellets or citric acid The powder mixture containing Tin is filled into the first capsule. Production method 3: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium mixture. One part of magnesium stearate is added to the mixture and you are mixed. KarLSLm is compressed between the rollers by the tight, tight, compression method (roller compaction).

Kompres edilenkar slm (granüller) elenir. Kalan magnezyum elenen granüllere eklenir ve kar stnlln. The compressed snow slime (granules) is sieved. The remaining magnesium is added to the sieved granules and profit stnlln.

Iç Içe Yerlestirilmis Kapsüllerin Hazîlangý Dabigatran eteksilat granülleri, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kapli sitrik asit pelletleri veya sitrik asit pelletleri veya sitrik asit içeren toz karsm, birinci kapsül içine doldurulur. Preparation of Nested Capsules Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule. placed and coated citric acid pellets or citric acid pellets or powder mixture containing citric acid, is filled into the first capsule.

Birinci Kapsül Içerigi Ag rl kça % Dabigatran eteksilat serbest baz › veya dabigatran eteksilatn farmasötik açidan kabul edilebilir tuzlar:: polimorflarl, solvatlar, 30.0 - 80'0 hidratlar veya esterleri Mikrokristalin selüloz 10.0 - 50.0 Hidroksipropil metil selüloz 10.0 - 30.0 Kolloidal Silikon dioksit 0.5 - 3.0 Kroskarmelloz sodyum 1.0 - 15.0 Magnezyum stearat 0.1 - 5.0 Ikinci Kapsül Içerigi Kapl J(Izole) Tartarik Asit Pelletleri / Tartarik Asit Pelletler / Tartarik Asit Içeren Toz 10.0 - 50.0 TOPLAM 100.0 Tartarik Asit Pelletlerinin Haz rlanis : Tartarik asit ve mikrokristalin selüloz karlst r Un ve bu kar stm, yas bir kütle elde etmek için hidroksipropil selüloz içeren izopropil alkol çözeltisine eklenir. Söz konusu yas kütle, pellet elde etmek üzere ekstrüzyona, sferonizasyona tabi tutulur, kurutulur ve elenir. First Capsule Content Weight % Dabigatran etexilate free base or dabigatran etexilate from a pharmaceutical perspective acceptable salts:: polymorphs, solvates, 30.0 - 80'0 hydrates or esters Microcrystalline cellulose 10.0 - 50.0 Hydroxypropyl methyl cellulose 10.0 - 30.0 Colloidal Silicon dioxide 0.5 - 3.0 Croscarmellose sodium 1.0 - 15.0 Magnesium stearate 0.1 - 5.0 Second Capsule Content Coated J(Isolated) Tartaric Acid Pellets / Tartaric Acid Pellets / Powder Containing Tartaric Acid 10.0 - 50.0 TOTAL 100.0 Preparation of Tartaric Acid Pellets: Tartaric acid and microcrystalline cellulose are mixed. Flour and this mixture are mixed to obtain a flat mass. It is added to the isopropyl alcohol solution containing hydroxypropyl cellulose. The aforementioned age mass, pellet It is extruded, spheronized, dried and sieved to obtain

Izole Tartarik Asit Pelletlerinin (Kapl Tartarik Asit Pelletleri) Haztnlan s : Izolasyon çözeltisinin haz rlan sl: Formül 1: Saf suya HPMC ve sukroz ilave edilir ve karlstnllr. Elde edilen kar's ma talk eklenir ve karstnlln. Preparation of Isolated Tartaric Acid Pellets (Coated Tartaric Acid Pellets): The prepared water of the isolation solution: Formula 1: HPMC and sucrose are added to pure water and mixed. Talc is added to the resulting snow and karstnlln.

Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve kar stlrlllr. Elde edilen karlslma talk eklenir ve kar st ni llri. Formula 2: HPMC and triethyl citrate are added to the pure water and mixed. Talc is added to the resulting mixture and snow st ni llri.

Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde karlstîlîr. Elde edilen karlSîna talk ve PEG 6000 ilave edilir ve homojenizatörde karßtfrilü. Formula 3: HPMC is added to the pure water and mixed in the homogenizer. The obtained karlSîna talc and PEG 6000 is added and mixed in the homogenizer.

Tartarik asit pelletleri, Formül 1 ila 3 arasindan seçilen izolasyon çözeltisi ile kaplan r. Tartaric acid pellets are coated with the isolation solution selected from Formulas 1 to 3.

Tartarik Asit Içeren Toz KaFsT'nîiîn Hazî'llang* Tartarik asit, spreyle kurutulmus Iaktoz, kolloidal silikon dioksit ve prejelatinize nisasta elenir ve kar'st r` Ilr. Magnezyum stearat eklenir ve 1-2 dakika daha kar'st'r llr. Üretim yöntemi 1: Dabigatran Eteksilat Granüllerinin Hazlnlan s Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karstîflm Bu karsrn su ile granül haline getirilir. Powder Containing Tartaric Acid KaFsT'nîiîn Hazî'llang* Tartaric acid, spray-dried lactose, colloidal silicon dioxide and pregelatinized starch are sieved ve kar'st r` Ilr. Magnesium stearate is added and mixed for another 1-2 minutes. Production method 1: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water.

Granüller 50°C'de kurutulur ve elenir. Kurutulmus granüllere magnezyum stearat ilave edilir ve karst »ni J lan. The granules are dried at 50°C and sieved. Magnesium stearate is added to the dried granules and karst »ni J lan.

Iç Içe Yerlestirilmis Kapsüllerin Haz'nlanls Kaplîartarik asit pelletleri veya tartarik asit pelletleri veya tartarik asit içeren toz kar'snt'îkinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve dabigatran eteksilat granülleri, birinci kapsüle doldurulur. Üretim yöntemi 2: Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karlstrllr. Toz kar s m suyla granül haline getirilir ve 50°C'Iik fîmida kurutulur. Magnezyum stearat eklenir ve 1-2 dakika daha kariýstFer. Toz karsLm mini tabletler seklinde basllliî. Pleasure of Nested Capsules Captive-artaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid, second filled into the capsule. The second capsule is placed inside the first capsule and dabigatran etexilate granules are filled into the first capsule. Production method 2: Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. Powder mixture is granulated with water and dried at 50°C. Add magnesium stearate and mix for another 1-2 minutes. Dust The mixture is titled in the form of mini tablets.

Iç Içe Yerlestirilmis Kapsüllerin Haz rllanls Kapl tartarik asit pelletleri veya tartarik asit pelletleri veya tartarik asit içeren toz kar's m' ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve mini tabletler formundaki dabigatran eteksilat birinci kapsüle doldurulur. Üretim yöntemi 3: Dabigatran Eteksilat Granüllerinin Hazlrlans Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum karstrllîl. Magnezyum stearatîn bir kêmlý karls ma eklenir ve karîstîlîl'li. KarlSIn, silindirler araslîsikstîma yöntemi (roller compaction) ile kompres edilir.. Preparation of Nested Capsules Coated tartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid. filled into the capsule. The second capsule is placed inside the first capsule and is in the form of mini-tablets. dabigatran etexilate is filled into the first capsule. Production method 3: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium karstrllyl. It is added to a mixture of magnesium stearate and from karîstîlîl. KarlSIn is compressed by roller compaction method.

Kompres edilen karlsm (granüller) elenir. Kalan magnezyum elenen granüllere eklenir ve kar stn lln. The compressed mixture (granules) is sieved. The remaining magnesium is added to the sieved granules and snow stn lln.

Iç Içe Yerlestirilmis Kapsüllerin Hazînlanîsf Kapljartarik asit pelletleri veya tartarik asit pelletleri veya tartarik asit içeren toz karîsîînjkinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve dabigatran eteksilat granülleri, birinci kapsüle doldurulur. The Preparation of Nested Capsules Capljartaric acid pellets or tartaric acid pellets or powder mixture containing tartaric acid filled into the capsule. The second capsule is placed inside the first capsule and dabigatran etexilate granules are filled into the first capsule.

Birinci Kapsül Içerigi Ag rl kça % Kapl. l(Izole) Tartarik Asit Pelletleri / Tartarik Asit Pelletleri / Tartarik Asit Içeren Toz 10.0 - 50.0 Karsmn Ikinci Kapsül Içerigi Dabigatran eteksilat serbest baz veya dabigatran eteksilatît farmasötik açldan .0 - 80.0 kabul edilebilir tuzlar;,S polimorflarl,j solvatlar;` hidratlar'Veya esterleri Mikrokristalin selüloz 10.0 - 50.0 Hidroksipropil metil selüloz 10.0 - 30.0 Kolloidal Silikon dioksit 0.5 - 3.0 Kroskarmelloz sodyum 1.0 - 15.0 Magnezyum stearat 0.1 - 5.0 TOPLAM 100.0 Tartarik Asit Pelletlerinin Haz rlanis : Tartarik asit ve mikrokristalin selüloz karlst r lln ve bu kar sm, yas bir kütle elde etmek için hidroksipropil selüloz içeren izopropil alkol çözeltisine eklenir. Söz konusu yas kütle, pellet vermek üzere ekstrüzyona, sferonizasyona tabi tutulur, kurutulur ve elenir. First Capsule Content Weight % cap. l(Isolated) Tartaric Acid Pellets / Tartaric Acid Pellets / Powder Containing Tartaric Acid 10.0 - 50.0 Karsmn Second Capsule Content Dabigatran etexilate free base or dabigatran etexilatît from the pharmaceutical point of view .0 - 80.0 acceptable salts, S polymorphs, j solvates; hydrates' or esters Microcrystalline cellulose 10.0 - 50.0 Hydroxypropyl methyl cellulose 10.0 - 30.0 Colloidal Silicon dioxide 0.5 - 3.0 Croscarmellose sodium 1.0 - 15.0 Magnesium stearate 0.1 - 5.0 TOTAL 100.0 Preparation of Tartaric Acid Pellets: Tartaric acid and microcrystalline cellulose are mixed and this mixture is used to obtain a smooth mass. It is added to the isopropyl alcohol solution containing hydroxypropyl cellulose. The aforementioned age mass, pellet It is extruded, spheronized, dried and sieved to give

Izole Tartarik Asit Pelletlerinin (KaplýTartarik Asit Pelletleri) Haziîilangî Izolasyon çözeltisinin hazrlanisL: Formül 1: Saf suya HPMC ve sukroz ilave edilir ve karlst'nllr. Elde edilen kar s'ma talk eklenir ve kar'St'rl'llrl. Preparation of Isolated Tartaric Acid Pellets (Coated Tartaric Acid Pellets) Preparation of the isolation solution: Formula 1: HPMC and sucrose are added to pure water and mixed. Talc is added to the resulting snow and kar'St'rl'llrl.

Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve karLstlrllir. Elde edilen karls ma talk eklenir ve kar st n lln. Formula 2: HPMC and triethyl citrate are added to pure water and mixed. Talc is added to the resulting mixture and karst n lln.

Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde karlst'nllr. Elde edilen karlSîma talk ve PEG 6000 ilave edilir ve homojenizatörde karTstTTTr. Formula 3: HPMC is added to the pure water and mixed in the homogenizer. The resulting mixed talc and PEG 6000 is added and mixed in the homogenizer.

Tartarik asit pelletleri, Formül 1 ila 3 arasindan seçilen izolasyon çözeltisi ile kaplan I. Tartaric acid pellets were coated with isolation solution selected from Formulas 1 to 3. I.

Tartarik Asit Içeren Toz Kars m'nn Haz rilans Tartarik asit, spreyle kurutulmus Iaktoz, kolloidal silikon dioksit ve prejelatinize nisasta elenir ve kar st r Ilr. Magnezyum stearat eklenir ve 1-2 dakika daha kar'st r llr. Üretim yöntemi 1: Dabigatran Eteksilat Granüllerinin Hazlrlan s Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve kar st r lln. Bu kars m su ile granül haline getirilir. Preparation of Powder Mixture Containing Tartaric Acid Tartaric acid, spray-dried lactose, colloidal silicon dioxide and pregelatinized starch are sieved and snow st r Ilr. Magnesium stearate is added and mixed for another 1-2 minutes. Production method 1: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium are sieved and mixed. This mixture is granulated with water.

Granüller 50°C'de kurutulur ve elenir. Kurutulmus granüllere magnezyum stearat ilave edilir ve karstiîm. The granules are dried at 50°C and sieved. Magnesium stearate is added to the dried granules and i am karst.

Iç Içe Yerlestirilmis Kapsüllerin Haz nlanls Dabigatran eteksilat granülleri, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kaplýtartarik asit pelletleri veya tartarik asit pelletleri veya tartarik asit içeren toz karîsün, birinci kapsül içine doldurulur. Üretim yöntemi 2: Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karlStT'l'if. Toz kar'S'TTn suyla granül haline getirilir ve 50°C'lik firimda kurutulur. Magnezyum stearat eklenir ve 1-2 dakika daha kar stirllr. Toz karsLm mini tabletler seklinde bastltr'. Preparation of Nested Capsules Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule. is placed and coated with tartaric acid pellets or tartaric acid pellets or powder containing tartaric acid. Karîsun is filled into the first capsule. Production method 2: Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium is sieved and mixed. Powder snow'S'TTn is granulated with water and dried at 50°C. Magnesium stearate is added and stirred for another 1-2 minutes. Dust The mixture is bastltr' in the form of mini tablets.

Iç Içe Yerlestirilmis Kapsüllerin Haz nlanls Mini tabletler formundaki dabigatran eteksilat, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kaplîartarik asit pelletleri veya tartarik asit pelletleri veya tartarik asit içeren toz karlsni, birinci kapsül içine doldurulur. Üretim yöntemi 3: Dabigatran Eteksilat Granüllerinin HazmlaniSi" Dabigatran eteksilat, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum karstTTFn. Magnezyum stearatTt bir ksmrkarßîna eklenir ve karîstmm KarEsEn, silindirler arasEsîkîstIma yöntemi (roller compaction) ile kompres edilir.. Preparation of Nested Capsules Dabigatran etexilate in the form of mini-tablets is filled into the second capsule. second capsule, first placed in the capsule and coated with capertaric acid pellets or tartaric acid pellets or tartaric acid pellets. The acid-containing powder mixture is filled into the first capsule. Production method 3: Ingestion of Dabigatran Ethexylate Granules" Dabigatran etexilate, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium karstTTFn. Magnesium stearate is added to a portion of Karîstmm KarEsEn is compressed by roller compaction method.

Kompres edilenkar Sim (granüller) elenir. Kalan magnezyum elenen granüllere eklenir ve kar stmlin. Compressed snow Sim (granules) is sieved. The remaining magnesium is added to the sieved granules and snow stmlin.

Iç Içe Yerlestirilmis Kapsüllerin Haz nlanls Dabigatran eteksilat granülleri, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kaplîartarik asit pelletleri veya tartarik asit pelletleri veya tartarik asit içeren toz karîsîm, birinci kapsül içine doldurulur. Preparation of Nested Capsules Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule. is placed and coated with artaric acid pellets or tartaric acid pellets or powder containing tartaric acid. The mixture is filled into the first capsule.

Bir uygulamaya göre, bulus, dabigatran eteksilatn bu farmasötik kompozisyonlardaki çözünürlülügünü arttirmak için, siklodekstrin veya polivinilpirolidon (PVP) veya polietilen glikol (PEG) veya bunlarm karýsümlarýnýkullanarak baska çözümler sunar. According to one embodiment, the invention features dabigatran etexilate in these pharmaceutical compositions. To increase its solubility, cyclodextrin or polyvinylpyrrolidone (PVP) or polyethylene glycol It offers other solutions using (PEG) or mixtures thereof.

Mevcut bulusun bir uygulamasîia göre, birinci formulasyonu ve ikinci formulasyonu içeren bahsedilen farmasötik kompozisyon; a) toplam kompozisyonda - ag rllkça %30.0-80.0 direkt trombin inhibitörü serbest bazln veya söz konusu inhibitörün farmasötik aç dan kabul edilebilir tuzlarm,I polimorflarinl, solvatlar.nl,i hidratlarln. l veya esterlerini; - ag ElEça %3.0-30.0 siklodekstrin veya PVP veya PEG veya bunlarîn karîsînlarj - ag Ilkça %5.0-50.0 seyreltici; - aglrl kça %0.1-3.0 glidant; - agirlkça %1 .0-15.0 dag'tcî - aglrl kça %0.1-5.0 lubrikan içeren birinci formulasyon b) toplam kompozisyonda - agirllkça %10.0-50.0 organik asit pelletleri veya kapl (izole) organik asit pelletleri veya organik asit içeren toz kar slm içeren ikinci formulasyon içermektedir. According to one embodiment of the present invention, comprising the first formulation and the second formulation. said pharmaceutical composition; a) in the total composition - 30.0-80.0% by weight direct thrombin inhibitor free base or pharmaceutically acceptable salts of inhibitor, polymorphs, solvates.nl, hydrates. l or its esters; - ag Eça 3.0-30.0% cyclodextrin or PVP or PEG or mixtures thereof - ag 5.0-50.0% diluent first; - 0.1-3.0% glidant by weight; - 1% .0-15.0% by weight - First formulation containing 0.1-5.0% lubricant by weight b) in the total composition - 10.0-50.0% by weight of organic acid pellets or coated (isolated) organic acid pellets or It contains a second formulation containing powdered snow powder containing organic acid.

Mevcut bulusun bir diger uygulamasîsöz konusu farmasötik kompozisyonu hazmama prosesi ile ilgili olup; bahsedilen proses asaglöaki admilarîçermektedir: a. Birinci formulasyon hazîlanî; i. Direkt trombin inhibitörü serbest baz_Veya söz konusu inhibitörün farmasötik açsdan kabul edilebilirtuzlar ,ipolimorflarr,isolvatlarl, hidratlar. Veya esterleri, birinci süspansiyonu elde etmek için bir çözücü ile süspande edilir; ii. Siklodekstrin veya PVP veya PEG veya bunlarTt karßînlarîikinci süspansiyonu elde etmek için bir çözücü ile süspande edilir; iii. Ad'm (ii)'de elde edilen ikinci süspansiyon, ad'm (i)'de elde edilen birinci süspansiyon üzerine, direkt trombin inhibitörü karls ml elde etmek için ilave edilir; iv. Seyreltici, baglaylc', glidant ve dag IlC, bir kar slm elde etmek için kar st rlln ve ögütülür; v. Adim (iii)'te elde edilen direkt trombin inhibitörü kars ml, ad m (iv)'te elde edilen karSWn ile granüller elde etmek için granüle edilir; vi. Adim (v)'de elde edilen granüller kurutulur ve Ögütülür; vii. Ad ;m (vi)'de elde edilen granüllere lubrikan ilave edilir ve karstrlm; b. Ikinci formulasyon haz rlanln; i. Organik asit ve tercihen en az bir farmasötik aç'dan kabul edilebilir eksipiyan karstmlm; ii. Ad LIn(i)”de elde edilen karSIn, organik asit pelletleri elde etmek üzere ekstrüzyona veya sferonizasyona tabi tutulur; iii. Istege bagl' olarak, organik asit pelletleri bir izolasyon çözeltisi ile kaplan'r; 0. Ikinci formülasyon ikinci kapsülün içine doldurulur ve; d. Ikinci kapsül birinci kapsülün içine yerlestirilir ve ard ndan birinci formülasyon birinci kapsüle Mevcut bulusun bir uygulamasîia göre, birinci formulasyonu ve ikinci formulasyonu içeren bahsedilen farmasötik kompozisyon; a) toplam kompozisyonda - ag rl kça %30.0-80.0 dabigatran eteksilat serbest bazlnl Neya dabigatran eteksilat n farmasötik açidan kabul edilebilir tuzlarlhlîl polimorflarmlî solvatlarhlîl hidratlarîti'* veya esterlerini; - ag Ilkça %3.0-30.0 siklodekstrin veya PVP veya PEG veya bunlarn karlsLmlar-;J - aglrl kça %5.0-50.0 mikrokristalin selüloz; - aglrl kça %1 .0-30.0 hidroksipropil metil selüloz; - aglrl kça %0.1-3.0 kolloidal silikon dioksit; - ag Frlkça %1 .O-15.0 kroskarmelloz sodyum; - ag Frl'kça %0.1-5.0 magnezyum stearat içeren birinci formulasyon b) toplam kompozisyonda - agrlkça %10.0-50.0 sitrik asit veya tartarik asit pelletleri veya kaplU(izole) sitrik asit veya tartarik asit pelletleri veya sitrik asit veya tartarik asit içeren toz kars m içeren ikinci formulasyon içermektedir. Another application of the present invention is the process of digesting the pharmaceutical composition in question. is related to; the mentioned process includes the following admilar: a. The first formulation is in preparation; I. Direct thrombin inhibitor free base_Or from a pharmaceutical point of view of the inhibitor in question acceptable salts, polymorphs, isolvates, hydrates. Or esters, obtain the first suspension suspended with a solvent to ii. Obtain the second suspension of cyclodextrin or PVP or PEG or their Tt suspended with a solvent to iii. The second suspension obtained in ad'm (ii), the first suspension obtained in ad'm (i) on the suspension, a direct thrombin inhibitor is added to obtain Karls ml; iv. The diluent, binder, glidant and mountain ILC are mixed to obtain a mixture and it is ground; v. Mix ml of direct thrombin inhibitor obtained in step (iii), compared with that obtained in step (iv) granulated to obtain granules with karSWn; vi. The granules obtained in step (v) are dried and ground; vii. Lubricant is added to the granules obtained in step (vi) and mixed; b. Prepare the second formulation; I. Organic acid and preferably at least one pharmaceutically acceptable excipient mixed; ii. The snow obtained in Ad LIn(i) is extruded to obtain organic acid pellets. or spheronized; iii. Optionally, the organic acid pellets are coated with an isolation solution; 0. The second formulation is filled into the second capsule and; D. The second capsule is placed inside the first capsule and then the first formulation is inserted into the first capsule. According to one embodiment of the present invention, comprising the first formulation and the second formulation. said pharmaceutical composition; a) in the total composition - 30.0-80.0% by weight dabigatran etexilate free base Ne or dabigatran etexilate pharmaceutically acceptable salts, polymorphs, solvates, hydrates, or esters; - w First 3.0-30.0% cyclodextrin or PVP or PEG or mixtures thereof-; - 5.0%-50.0% by weight microcrystalline cellulose; - 1% .0-30.0% hydroxypropyl methyl cellulose by weight; - 0.1-3.0% by weight colloidal silicon dioxide; - ag 1% .O-15.0 croscarmellose sodium; - First formulation containing 0.1-5.0% magnesium stearate by ag Frl b) in the total composition - 10.0-50.0% by weight citric acid or tartaric acid pellets or coated (isolated) citric acid or a second containing tartaric acid pellets or a powder mixture containing citric acid or tartaric acid. contains formulation.

Mevcut bulusun bir diger uygulamasîsöz konusu farmasötik kompozisyonu hazîlama prosesi ile ilgili olup; bahsedilen proses asagldaki adlmlar içermektedir: a. Birinci formulasyon haz rlan r; i. Dabigatran eteksilat serbest baz veya dabigatran eteksilat ni farmasötik aç olan kabul edilebilir tuzlar ,l polimorflar, solvatlar , hidratlarl lveya esterleri, birinci süspansiyonu elde etmek için etil alkol, 2-propanol veya bunlaan karlSlmlar'nl içeren bir gruptan seçilecek bir çözücü ile süspande edilir; ii. Siklodekstrin veya PVP veya PEG veya bunlarît karüsînlarÇIKInci süspansiyonu elde etmek için bir su ile süspande edilir; iii. Ad m (ii)'de elde edilen ikinci süspansiyon, adem (i)'de elde edilen birinci süspansiyon üzerine, dabigatran eteksilat kar's ml elde etmek için ilave edilir; iv. Mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum, bir karISIfn elde etmek için karStIJ'JJE ve ögütülür; v. AdIn (iii)'te elde edilen dabigatran eteksilat karßîn, adtî'n (iv)'te elde edilen karLSIn ile granüller elde etmek için granüle edilir; vi. Adim (v)'de elde edilen granüller kurutulur ve ögütülür; vii. Ad m (vi)ide elde edilen granüllere magnezyum stearat ilave edilir ve karlst r lln; b. Ikinci formulasyon haz rlanln; i. Sitrik asit veya tartarik asit ve tercihen en az bir farmasötik aç dan kabul edilebilir eksipiyan karSthTr; ii. Ad In(i)'de elde edilen karîsîn, sitrik asit veya tartarik asit pelletleri elde etmek üzere ekstrüzyona veya sferonizasyona tabi tutulur; iii. Istege bagl lolarak, sitrik asit veya tartarik asit pelletleri bir izolasyon çözeltisi ile kaplan r; 0. Ikinci formülasyon ikinci kapsülün içine doldurulur ve; d. Ikinci kapsül birinci kapsülün içine yerlestirilir ve ard ndan birinci formülasyon birinci kapsüle Mevcut bulusun bir uygulamasina göre, birinci formulasyonu ve ikinci formulasyonu içeren bahsedilen farmasötik kompozisyon; a) toplam kompozisyonda - ag Tlmça %10.0-50.0 organik asit pelletleri veya kaplî(izole) organik asit pelletleri veya organik asit içeren toz kerîsmn içeren birinci formulasyon b) toplam kompozisyonda - ag rllkça %30.0-80.0 direkt trombin inhibitörü serbest bazlm veya söz konusu inhibitörün farmasötik açdan kabul edilebilir tuzlarnm polimorflarTtT, solvatlarhi hidratlarmî veya esterlerini; - ag Elkça %3.0-30.0 siklodekstrin veya PVP veya PEG veya bunlarIi karüsînlarj - aglrl kça %5.0-50.0 seyreltici; - aglrl kça %0.1-3.0 glidant; içeren ikinci formulasyon içermektedir. Another application of the present invention is the process of preparing said pharmaceutical composition. is related to; The mentioned process includes the following steps: a. The first formulation is prepared; I. Dabigatran etexilate free base or dabigatran etexilate is considered pharmaceutically hungry soluble salts, polymorphs, solvates, hydrates or esters to obtain the first suspension to be selected from the group consisting of ethyl alcohol, 2-propanol or mixtures thereof. suspended with solvent; ii. Obtain cyclodextrin or PVP or PEG or their carucines OUTPUT suspension suspended with a water to iii. The second suspension obtained in step m (ii), the first suspension obtained in step (i) dabigatran etexilate is added onto the suspension to obtain 1 ml of snow; iv. Microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium is mixed and ground to obtain a mixture; v. Dabigatran etexilate obtained in AdIn (iii), whereas the profit obtained in adtî'n (iv) granulated to obtain granules; vi. The granules obtained in step (v) are dried and ground; vii. Magnesium stearate is added to the granules obtained in step (vi) and mixed. b. Prepare the second formulation; I. Citric acid or tartaric acid and preferably at least one pharmaceutically acceptable excipient snowSthTr; ii. To obtain pellets of carcin, citric acid or tartaric acid obtained in Ad In(i). subjected to extrusion or spheronization; iii. Optionally, citric acid or tartaric acid pellets are mixed with an isolation solution. tiger r; 0. The second formulation is filled into the second capsule and; D. The second capsule is placed inside the first capsule and then the first formulation is inserted into the first capsule. According to one embodiment of the present invention, comprising the first formulation and the second formulation said pharmaceutical composition; a) in the total composition - 10.0-50.0% organic acid pellets or coated (isolated) organic acid pellets in ag Tlm or First formulation containing powdered carbuncle containing organic acid b) in the total composition - 30.0-80.0% by weight direct thrombin inhibitor free base or said polymorphs of the pharmaceutically acceptable salts of the inhibitor, TtT, solvates, hydrates or its esters; - ag Elk 3.0-30.0% cyclodextrin or PVP or PEG or carucines with these - 5.0%-50.0% diluent by weight; - 0.1-3.0% glidant by weight; Contains a second formulation containing

Mevcut bulusun bir diger uygulamas t, söz konusu farmasötik kompozisyonu hazLrilama prosesi ile ilgili olup; bahsedilen proses asagidaki adimlar içermektedir: a. Birinci formulasyon haz'rlan r; i. Organik asit ve tercihen en az bir farmasötik açöan kabul edilebilir eksipiyan karstmlm; ii. Adin(i)'de elde edilen karSIn, organik asit pelletleri elde etmek üzere ekstrüzyona veya sferonizasyona tabi tutulur; iii. Istege bagl olarak, organik asit pelletleri bir izolasyon çözeltisi ile kaplan r; b. Ikinci formulasyon haz rlanln; i. Direkt trombin inhibitörü serbest baz veya söz konusu inhibitörün farmasötik aç dan kabul edilebilirtuzlar ,lpolimorflar ,solvatlarl, hidratlar Veya esterleri, birinci süspansiyonu elde etmek için bir çözücü ile süspande edilir; ii. Siklodekstrin veya PVP veya PEG veya bunlarI] karßînlarjkinci süspansiyonu elde etmek için bir çözücü ile süspande edilir; iii. Ad'm (ii)'de elde edilen ikinci süspansiyon, adim (i)'de elde edilen birinci süspansiyon üzerine, bir direkt trombin inhibitörü karis ml elde etmek için ilave edilir; iv. Seyreltici, baglayîcî glidant ve dag 'tlöî bir karsmi elde etmek için karStTlTri ve ögütülür; v. AdLm (iii)'te elde edilen direkt trombin inhibitörü karsmt, adm (Iv)'te elde edilen kar slm ile granüller elde etmek için granüle edilir; vi. Adim (v)'de elde edilen granüller kurutulur ve ögütülür; vii. Ad m (vi)'de elde edilen granüllere Iubrikan ilave edilir ve kar str un; 0. Ikinci formülasyon ikinci kapsülün içine doldurulur ve; d. Ikinci kapsül birinci kapsülün içine yerlestirilir ve ard hdan birinci formülasyon birinci kapsüle Mevcut bulusun bir uygulamasina göre, birinci formulasyonu ve ikinci formulasyonu içeren bahsedilen farmasötik kompozisyon; a) toplam kompozisyonda - ag Ilkça %10.0-50.0 sitrik asit veya tartarik asit pelletleri veya kaplüûzole) sitrik asit veya tartarik asit pelletleri veya sitrik asit veya tartarik asit içeren toz karlSlm içeren birinci formulasyon; b) toplam kompozisyonda - ag rI kça %30.0-80.0 dabigatran eteksilat serbest bazlnl Neya dabigatran eteksilat n farmasötik aç dan kabul edilebilir tuzlarnm polimorflarnl, solvatlar ni,i hidratlar ni. veya esterlerini; - ag Ürlltça %3.0-30.0 siklodekstrin veya PVP veya PEG veya bunlarin karfsînlarj - ag Iltkça %5.0-50.0 mikrokristalin selüloz; - ag rl kça %1 .0-30.0 hidroksipropil metil selüloz; - aglrl'kça %0.1-3.0 kolloidal silikon dioksit; - ag Trlkça %1 .0-15.0 kroskarmelloz sodyum; - ag Lîlkça %0.1-5.0 magnezyum stearat içeren ikinci formulasyon içermektedir. Another application of the present invention is the process of preparing said pharmaceutical composition. is related to; The mentioned process includes the following steps: a. The first formulation is prepared; I. Organic acid and preferably at least one pharmaceutically acceptable excipient mixed; ii. The snow obtained in adin(i) is extruded to obtain organic acid pellets. or spheronized; iii. Optionally, organic acid pellets are coated with an isolation solution; b. Prepare the second formulation; I. The direct thrombin inhibitor free base or the pharmaceutical acceptable salts, polymorphs, solvates, hydrates or esters, obtain the first suspension suspended with a solvent to ii. cyclodextrin or PVP or PEG or their] second suspension is obtained. suspended with a solvent to iii. The second suspension obtained in step (ii) is the first suspension obtained in step (i). a direct thrombin inhibitor is added onto the suspension to obtain a mixture ml; iv. To obtain a mixture of diluent, binder, glidant and mountain, mix StTlTri and it is ground; v. Direct thrombin inhibitor mixture obtained in AdLm (iii), compared to that obtained in adm (Iv) granulated to obtain granules with snow silm; vi. The granules obtained in step (v) are dried and ground; vii. Iubrikan is added to the granules obtained in step m (vi) and snow str flour; 0. The second formulation is filled into the second capsule and; D. The second capsule is placed inside the first capsule and then the first formulation is inserted into the first capsule. According to one embodiment of the present invention, comprising the first formulation and the second formulation said pharmaceutical composition; a) in the total composition - ag 10.0-50.0% first citric acid or tartaric acid pellets or coated) citric acid or first containing tartaric acid pellets or a powder mixture containing citric acid or tartaric acid. formulation; b) in the total composition - 30.0-80.0% by weight dabigatran etexilate free base Ne or dabigatran etexilate n polymorphs of pharmaceutically acceptable salts, solvates, hydrates. or esters; - 3.0-30.0% cyclodextrin or PVP or PEG or their carfsines by ag Product - ag 5.0%-50.0 microcrystalline cellulose; - 1% .0-30.0% by weight of hydroxypropyl methyl cellulose; - 0.1-3.0% by weight colloidal silicon dioxide; - ag 1% .0-15.0 croscarmellose sodium per swt; - Contains a second formulation containing 0.1-5.0% magnesium stearate by weight.

Mevcut bulusun bir diger uygulamas', söz konusu farmasötik kompozisyonu hazirîlama prosesi ile ilgili olup; bahsedilen proses asagldaki adlmlar içermektedir: 3. Birinci formulasyon haz rlan r; i. Sitrik asit veya tartarik asit ve tercihen en az bir farmasötik aç dan kabul edilebilir eksipiyan kar Stlrlllr; ii. Ad.m(i)'de elde edilen kar Sim, sitrik asit veya tartarik asit pelletleri elde etmek üzere ekstrüzyona veya sferonizasyona tabi tutulur; iii. Istege baglJolarak, sitrik asit veya tartarik asit pelletleri bir izolasyon çözeltisi ile kaplan r; b. Ikinci formulasyon haz rlanlr; i. Dabigatran eteksilat serbest baz *Veya dabigatran eteksilatîti farmasötik aç'dan kabul edilebilir tuzlar ,1 polimorflar, solvatlar , hidratlarl lveya esterleri, birinci süspansiyonu elde etmek için etil alkol, 2-propanol veya bunlaan karlslmlarnLiçeren bir gruptan seçilecek bir çözücü ile süspande edilir; ii. Siklodekstrin veya PVP veya PEG veya bunlar n karls mlar , ikinci süspansiyonu elde etmek için bir su ile süspande edilir; iii. AdTn (ii)'de elde edilen ikinci süspansiyon, adîm (i)'de elde edilen birinci süspansiyon üzerine, bir dabigatran eteksilat karFsTnîelde etmek için ilave edilir; iv. Mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum, bir kar;s,m elde etmek için karstrlli: ve ögütülür; v. Ad m (iii)'te elde edilen dabigatran eteksilat karlSim, adim (iv)'te elde edilen karis m ile granüller elde etmek için granüle edilir; vi. Ade (v)'de elde edilen granüller kurutulur ve ögütülür; vii. AdIn (vi)'de elde edilen granüllere magnezyum stearat ilave edilir ve karStIJE; 0. Ikinci formülasyon ikinci kapsülün içine doldurulur ve; d. Ikinci kapsül birinci kapsülün içine yerlestirilir ve ard ndan birinci formülasyon birinci kapsüle Birinci Kapsül Içerigi Ag rl kça % Dabigatran eteksilat serbest baz veya dabigatran eteksilatn farmasötik açidan .0 - 80.0 kabul edilebilir tuzlar: polimorflarÇ solvatlar: hidratlarzveya esterleri Siklodekstrin veya PVP veya PEG veya 3.0 - 30.0 bunlar ni kar s mlar Mikrokristalin selüloz 5.0 - 50.0 Hidroksipropil metil selüloz 1.0 - 30.0 Kolloidal Silikon dioksit 0.1 - 3.0 Kroskarmelloz sodyum 1.0 - 15.0 Magnezyum stearat 0.1 - 5.0 Ikinci Kapsül Içerigi Kaplî(IzoIe) Organik Asit Pelletleri / Organik Asit Pelletleri / Organik Asit Içeren Toz 10.0-50.0 TOPLAM 100.0 Organik Asit Pelletlerinin Haz rlan sI: Organik asit ve mikrokristalin selüloz kar St'rlllr ve bu kar s m, yas bir kütle elde etmek için hidroksipropil selüloz içeren izopropil alkol çözeltisine eklenir. Söz konusu yas kütle, pellet elde etmek üzere ekstrüzyona, sferonizasyona tabi tutulur, kurutulur ve elenir. Another application of the present invention is the process of preparing said pharmaceutical composition. is related to; The mentioned process includes the following steps: 3. The first formulation is prepared; I. Citric acid or tartaric acid and preferably at least one pharmaceutically acceptable excipient snow Strlllr; ii. The snow obtained in Ad.m(i) is used to obtain pellets of Sim, citric acid or tartaric acid. subjected to extrusion or spheronization; iii. Optionally, citric acid or tartaric acid pellets are mixed with an isolation solution. tiger r; b. The second formulation is prepared; I. Dabigatran etexilate free base *Or dabigatran etexilate pharmaceutically acceptable salts, 1 polymorphs, solvates, hydrates or esters, obtain the first suspension to be selected from a group consisting of ethyl alcohol, 2-propanol or mixtures thereof. suspended with solvent; ii. Cyclodextrin or PVP or PEG, or mixtures thereof, yield the second suspension. suspended with a water to iii. The second suspension obtained in AdTn (ii) is the first suspension obtained in step (i). added onto the suspension to obtain a dabigatran etexilate mixture; iv. Microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium is mixed and ground to obtain a mixture; v. The dabigatran etexilate mixture obtained in step m (iii), the mixture obtained in step (iv) granulated to obtain granules; vi. The granules obtained in Ade (v) are dried and ground; vii. Magnesium stearate is added to the granules obtained in AdIn (vi) and karStIJE; 0. The second formulation is filled into the second capsule and; D. The second capsule is placed inside the first capsule and then the first formulation is inserted into the first capsule. First Capsule Content Weight % Dabigatran etexilate free base or dabigatran etexilate from a pharmaceutical perspective .0 - 80.0 acceptable salts: polymorphsÇ solvates: hydrates or esters Cyclodextrin or PVP or PEG or 3.0 - 30.0 what do they look like Microcrystalline cellulose 5.0 - 50.0 Hydroxypropyl methyl cellulose 1.0 - 30.0 Colloidal Silicon dioxide 0.1 - 3.0 Croscarmellose sodium 1.0 - 15.0 Magnesium stearate 0.1 - 5.0 Second Capsule Content Coated(Isolated) Organic Acid Pellets / Organic Acid Pellets / Powder Containing Organic Acids 10.0-50.0 TOTAL 100.0 Preparation of Organic Acid Pellets: Organic acid and microcrystalline cellulose snow are stabilized and this mixture is used to obtain a flat mass. It is added to the isopropyl alcohol solution containing hydroxypropyl cellulose. The aforementioned age mass is obtained from pellets. It is extruded, spheronized, dried and sieved.

Izole Organik Asit Pelletlerinin (KaplEOrganik Asit Pelletleri) Hazîlang: Izolasyon çözeltisinin haz rlan si: Formül 1: Saf suya HPMC ve sukroz ilave edilir ve karist'hllr. Elde edilen kar sma talk eklenir ve karýstîl'm. Hazîlang of Isolated Organic Acid Pellets (Coated Organic Acid Pellets): Preparation of the isolation solution: Formula 1: HPMC and sucrose are added to pure water and mixed. Talc is added to the resulting snow and i am karıstîl.

Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve karstmtf. Elde edilen karîsîna talk eklenir ve kar'st'n Im. Formula 2: HPMC and triethyl citrate are added to pure water and mixed. Talc is added to the obtained wife and kar'st'n Im.

Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde kanst n llr. Elde edilen kansma talk ve PEG 6000 ilave edilir ve homojenizatörde kanst r lIr. Formula 3: HPMC is added to the pure water and mixed in the homogenizer. The resulting mixture of talc and PEG 6000 is added and mixed in the homogenizer.

Organik asit pelletleri, Formül 1 ila 3 aras ndan seçilen izolasyon çözeltisi ile kaplan r. Organic acid pellets are coated with the isolation solution selected from Formulas 1 to 3.

Organik Asit Içeren Toz Kar Sim n.n Hazirlan s. 1 Organik asit, spreyle kurutulmus Iaktoz, kolloidal silikon dioksit ve prejelatinize nisasta elenir ve karîstîlî. Magnezyum stearat eklenir ve 1-2 dakika daha karstirîl'm Üretim yöntemi 1: Dabigatran Eteksilat Granüllerinin Hazlrlanis Dabigatran eteksilat, etil alkol veya 2-pr0pan0l ile süspande edilir. Siklodekstrin veya PVP veya PEG, su ile süspande edilir. Siklodekstrin veya PVP veya PEG süspansiyonu 30-35°C`de etil alkol veya 2-propanol ile süspande edilmis dabigatran eteksilat üzerine ilave edilir. Powder Snow Glitter Containing Organic Acids Prepare p. one Organic acid, spray-dried lactose, colloidal silicon dioxide and pregelatinized starch are sieved and karistili. Magnesium stearate is added and mixed for another 1-2 minutes. Production method 1: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate is suspended with ethyl alcohol or 2-propanol. Cyclodextrin or PVP or PEG is suspended with water. Cyclodextrin or PVP or PEG suspension ethyl at 30-35°C Added to dabigatran etexilate suspended with alcohol or 2-propanol.

Mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve kar st r [in ve ard ndan dabigatran eteksilat karlSIm yla kar st r lin ve granüle edilir. Granüller 55°C'de kurutulur ve elenir. Kurutulmus granüllere magnezyum stearat ilave edilir ve karýstîillî. Microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose the sodium is sieved and mixed with a mixture of salt and then a mixture of dabigatran etexilate and is granulated. The granules are dried at 55 °C and sieved. Magnesium stearate into dried granules added and karıstîilli.

Iç Içe Yerlestirilmis Kapsüllerin Hazorilanls Kapl organik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz kar s m' 1 ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve dabigatran eteksilat granülleri, birinci kapsüle doldurulur. Üretim yöntemi 2: Dabigatran eteksilat, etil alkol veya 2-propanol ile süspande edilir. Siklodekstrin veya PVP veya PEG, su ile süspande edilir. Siklodekstrin veya PVP veya PEG süspansiyonu 30-35°C'de etil alkol veya 2-propanol ile süspande edilmis dabigatran eteksilat üzerine ilave edilir. Hazorilanls of Nested Capsules Coated organic acid pellets or organic acid pellets or powder mix containing organic acid filled into the second capsule. The second capsule is placed inside the first capsule and dabigatran etexilate granules are filled into the first capsule. Production method 2: Dabigatran etexilate is suspended with ethyl alcohol or 2-propanol. Cyclodextrin or PVP or PEG is suspended with water. Cyclodextrin or PVP or PEG suspension ethyl at 30-35°C Added to dabigatran etexilate suspended with alcohol or 2-propanol.

Mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karstîîllîrl ve ard Iidan dabigatran eteksilat karßînýla karstîilm ve granüle edilir. Granüller 55°C'de kurutulur ve elenir. Magnezyum stearat eklenir ve 1-2 dakika daha kar stirillr. Toz karisim mini tabletler seklinde bas llr. Microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium is sieved and mixed with karstîllîrl and then dabigatran etexilate and is granulated. The granules are dried at 55 °C and sieved. Magnesium stearate is added and for 1-2 minutes more profitable. The powder mixture is pressed as mini-tablets.

Iç Içe Yerlestirilmis Kapsüllerin Hazînlanîsf Kaplîorganik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz karSInJ ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve mini tabletler formundaki dabigatran eteksilat birinci kapsüle doldurulur. Üretim yöntemi 3: Dabigatran Eteksilat Granüllerinin Hazirilanis Dabigatran eteksilat, Siklodekstrin veya PVP veya PEG, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum ve magnezyum stearatm yaris: karstnlm ve ögütülür. Karsm, silindirler aras,s.k,stlrma yöntemi (roller compaction) ile kompres edilir. Kompres edilen kar slm (granüller) elenir. Kalan magnezyum elenen granüllere eklenir ve kariSt'r Im. The Preparation of Nested Capsules Coated organic acid pellets or organic acid pellets or powder mixture containing organic acid filled into the second capsule. The second capsule is placed inside the first capsule and the mini-tablets dabigatran etexilate in the form of is filled into the first capsule. Production method 3: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate, Cyclodextrin or PVP or PEG, microcrystalline cellulose, hydroxypropyl Competing with methyl cellulose, colloidal silicon dioxide and croscarmellose sodium and magnesium stearate: mixed and ground. The mixture is mixed between the cylinders, by compaction method (roller compaction). is compressed. The compressed snow slurry (granules) is sieved. Remaining magnesium to sieved granules added and karSt'r Im.

Iç Içe Yerlestirilmis Kapsüllerin Hazîilanfs: Kaplîorganik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz karîsînj ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve dabigatran eteksilat granülleri, birinci kapsüle doldurulur. Preparation of Nested Capsules: Coated organic acid pellets or organic acid pellets or powder mixture containing organic acid filled into the second capsule. The second capsule is placed inside the first capsule and dabigatran etexilate granules are filled into the first capsule.

Birinci Kapsül Içerigi Ag'rjl'kça % Kapl. S(Izole) Organik Asit Pelletleri / Organik Asit Pelletleri / Organik Asit Içeren Toz 10.0 - 50.0 Ikinci Kapsül Içerigi Dabigatran eteksilat serbest baz veya dabigatran eteksilatn farmasötik açidan .0 - 80.0 kabul edilebilir tuzlar, polimorflari,` solvatlar, hidratlar veya esterleri Siklodekstrin veya PVP veya PEG veya 3.0 - 30.0 bunlarin kar smlar Mikrokristalin selüloz 5.0 - 50.0 Hidroksipropil metil selüloz 1.0 - 30.0 Kolloidal Silikon dioksit 0.1 - 3.0 Kroskarmelloz sodyum 1.0 - 15.0 Magnezyum stearat 0.1 - 5.0 TOPLAM 100.0 Organik Asit Pelletlerinin Hazî'lan'SE Organik asit ve mikrokristalin selüloz karStTi'lW ve bu karST'n, yas bir kütle elde etmek için hidroksipropil selüloz içeren izopropil alkol çözeltisine eklenir. Söz konusu yas kütle, pellet elde etmek üzere ekstrüzyona, sferonizasyona tabi tutulur, kurutulur ve elenir. First Capsule Content Weight % cap. S(Isolated) Organic Acid Pellets / Organic Acid Pellets / Powder Containing Organic Acids 10.0 - 50.0 Second Capsule Content Dabigatran etexilate free base or dabigatran etexilate from a pharmaceutical perspective .0 - 80.0 acceptable salts, polymorphs, solvates, hydrates or esters Cyclodextrin or PVP or PEG or 3.0 - 30.0 profits of these Microcrystalline cellulose 5.0 - 50.0 Hydroxypropyl methyl cellulose 1.0 - 30.0 Colloidal Silicon dioxide 0.1 - 3.0 Croscarmellose sodium 1.0 - 15.0 Magnesium stearate 0.1 - 5.0 TOTAL 100.0 Presence of Organic Acid Pellets Organic acid and microcrystalline cellulose karStTi'lW and this karST'n were used to obtain a flat mass. It is added to the isopropyl alcohol solution containing hydroxypropyl cellulose. The aforementioned age mass is obtained from pellets. It is extruded, spheronized, dried and sieved.

Izole Organik Asit Pelletlerinin (Kapli Organik Asit Pelletleri) Haz rlan s : Izolasyon çözeltisinin haz rlan si: Formül 1: Saf suya HPMC ve sukroz ilave edilir ve karstniir. Elde edilen karsrma talk eklenir ve kar str. Im“. Preparation of Isolated Organic Acid Pellets (Coated Organic Acid Pellets): Preparation of the isolation solution: Formula 1: HPMC and sucrose are added to pure water and mixed. Talc is added to the resulting mixture and snow str. Im“.

Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve kar st'rillr. Elde edilen kar'sma talk eklenir ve kar's't'r Im. Formula 2: HPMC and triethyl citrate are added to the pure water and the snow is st'rillr. Talc is added to the obtained snow and kar's't'r Im.

Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde kar'st'rlir. Elde edilen kar'Sîma talk ve PEG 6000 ilave edilir ve homojenizatörde karist r lIr. Formula 3: HPMC is added to pure water and mixed in the homogenizer. The obtained kar'Sîma talc and PEG 6000 is added and mixed in the homogenizer.

Organik asit pelletleri, Formül 1 ila 3 aras ndan seçilen izolasyon çözeltisi ile kaplanlr. The organic acid pellets are coated with the isolation solution selected from Formulas 1 to 3.

Organik Asit Içeren Toz Kar Sim n:n Hazirlans l Organik asit, spreyle kurutulmus laktoz, kolloidal silikon dioksit ve prejelatinize nisasta elenir ve kar;str;Jtr. Magnezyum stearat eklenir ve 1-2 dakika daha kanstrltrj. Üretim yöntemi 1: Dabigatran Eteksilat Granüllerinin Hazlî'ilanîs* Dabigatran eteksilat, etil alkol veya 2-propanol ile süspande edilir. Siklodekstrin veya PVP veya PEG, su ile süspande edilir. Siklodekstrin veya PVP veya PEG süspansiyonu 30-35°C'de etil alkol veya 2-propanol ile süspande edilmis dabigatran eteksilat üzerine ilave edilir. Powder Snow Glitter Containing Organic Acid n:n Preparation l The organic acid, spray-dried lactose, colloidal silicon dioxide and pregelatinized starch are sieved. and snow;str;Jtr. Magnesium stearate is added and mixed for another 1-2 minutes. Production method 1: Hazlî'ilanîs of Dabigatran Ethexylate Granules* Dabigatran etexilate is suspended with ethyl alcohol or 2-propanol. Cyclodextrin or PVP or PEG is suspended with water. Cyclodextrin or PVP or PEG suspension ethyl at 30-35°C Added to dabigatran etexilate suspended with alcohol or 2-propanol.

Mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve kar st r lln ve ard ndan dabigatran eteksilat karls m yla kar st r lln ve granüle edilir. Granüller 55°C'de kurutulur ve elenir. Kurutulmus granüllere magnezyum stearat ilave edilir ve karsti'lW. Microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose the sodium is sieved and stirred, and then mixed with the dabigatran etexilate mixture and is granulated. The granules are dried at 55 °C and sieved. Magnesium stearate into dried granules is added and karsti'lW.

Iç Içe Yerlestirilmis Kapsüllerin Hazrilants; Dabigatran eteksilat granülleri, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kaplîorganik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz karsrn, birinci kapsül içine doldurulur. Üretim yöntemi 2: Dabigatran eteksilat, etil alkol veya 2-propanol ile süspande edilir. Siklodekstrin veya PVP veya PEG, su ile süspande edilir. Siklodekstrin veya PVP veya PEG süspansiyonu 30-35°C'de etil alkol veya 2-propanol ile süspande edilmis dabigatran eteksilat üzerine ilave edilir. Preparations of Nested Capsules; Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule. are placed and coated with organic acid pellets or organic acid pellets or containing organic acid. The powder mixture is filled into the first capsule. Production method 2: Dabigatran etexilate is suspended with ethyl alcohol or 2-propanol. Cyclodextrin or PVP or PEG is suspended with water. Cyclodextrin or PVP or PEG suspension ethyl at 30-35°C Added to dabigatran etexilate suspended with alcohol or 2-propanol.

Mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum elekten geçirilir ve karstîîllît ve ard Ttdan dabigatran eteksilat karßînyla karstîîlm ve granüle edilir. Granüller 55°C`de kurutulur ve elenir. Magnezyum stearat eklenir ve 1-2 dakika daha karstlrlllr. Toz karlstm mini tabletler seklinde bas tir. Microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium is sieved and mixed with karstîllît and then dabigatran etexilate and is granulated. The granules are dried at 55 °C and sieved. Magnesium stearate is added and for 1-2 minutes they are more mixed. Press in the form of powder-mixed mini-tablets.

Iç Içe Yerlestirilmis Kapsüllerin Haz'nlanls Mini tabletler formundaki dabigatran eteksilat, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kaplEOrganik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz karÜSIri, birinci kapsül içine doldurulur. Üretim yöntemi 3: Dabigatran Eteksilat Granüllerinin Hazlrlanls Dabigatran eteksilat, siklodekstrin veya PVP veya PEG, mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum ve magnezyum stearatm yarBj karstmlln ve ögütülür. Kar;s;m, silindirler aras;s;k'stLr_ma yöntemi (roller compaction) ile kompres edilir. Kompres edilen kar slm (granüller) elenir. Kalan magnezyum elenen granüllere eklenir ve karlSt r Im. Pleasure of Nested Capsules Dabigatran etexilate in the form of mini-tablets is filled into the second capsule. second capsule, first placed in the capsule and coated with organic acid pellets or organic acid pellets or organic The acid-containing powder mix is filled into the first capsule. Production method 3: Preparation of Dabigatran Ethexylate Granules Dabigatran etexilate, cyclodextrin or PVP or PEG, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide, and croscarmellose sodium and magnesium stearate mixed and ground. Kar;s;m, between cylinders;s;k'stLr_ma method (roller compaction) is compressed. The compressed snow slurry (granules) is sieved. Remaining magnesium to sieved granules is added and karlSt r Im.

Iç Içe Yerlestirilmis Kapsüllerin Hazîllanîs* Dabigatran eteksilat granülleri, ikinci kapsüle doldurulur. Ikinci kapsül, birinci kapsülün içine yerlestirilir ve kapl *organik asit pelletleri veya organik asit pelletleri veya organik asit içeren toz karis m, birinci kapsül içine doldurulur. Preparation of Nested Capsules* Dabigatran etexilate granules are filled into the second capsule. The second capsule is inserted into the first capsule. placed and covered *organic acid pellets or organic acid pellets or containing organic acid The powder mix is filled into the first capsule.

Yukarlda 11 ile 12 aras nda verilen örneklerde bulusun bir baska uygulamaslna göre, organik asit, sitrik asit, tartarik asit, galik asit, orotik asit, p-kumarik asit, hipürik asit, ferulik asit, vanilik asit, fumarik asit, maleik asit, süksinik asit, sitrik asit, malik asit, glutamik asit, aspartik asit, oksalik asit, Iaktik asit, formik asit, asetik asit, propionik asit, kaproik asit, benzoik asit, karbonik asit, adipik asit veya bunlarn kar slmlarnl içeren bir gruptan seçilir. Tercihen, organik asit, sitrik asit veya tartarik asit veya bunlar n karis mlarldln. According to another embodiment of the invention in the examples given above 11 to 12, organic acid, citric acid, tartaric acid, gallic acid, orotic acid, p-coumaric acid, hipuric acid, ferulic acid, vanillic acid, fumaric acid, maleic acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid, oxalic acid, lactic acid, formic acid, acetic acid, propionic acid, caproic acid, benzoic acid, carbonic acid is selected from the group consisting of adipic acid or mixtures thereof. Preferably, organic acid, citric acid or tartaric acid or a mixture of these.

Claims (1)

  1. CLAIMS . A pharmaceutical composition in a dosage unit form comprising a first capsule and a second capsule which is located within the first capsule, wherein the first capsule comprising a first formulation held between the first and second capsule and comprising a second formulation held in the second capsule, and wherein the first formulation or the second formulation comprising a direct thrombin inhibitor in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof or at least one organic acid. . The pharmaceutical composition according to claim 1, wherein the first formulation and the second formulation are in the form of mini tablets or granules or pellets or powder or beads or capsules or mixtures thereof. . The pharmaceutical composition according to claim 1, wherein the direct thrombin inhibitor is dabigatran etexilate in the form of free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof. . The pharmaceutical composition according to claim 1, wherein the organic acid is selected from a group comprising citric acid, tartaric acid, gallic acid, orotic acid, p- coumaric acid, hippuric acid, ferulic acid, vanillic acid, fumaric acid, maleic acid, succinic acid, malic acid, glutamic acid, aspartic acid, oxalic acid, Iactic acid, formic acid, acetic acid, propionic acid, caproic acid, benzoic acid, carbonic acid, adipic acid or mixtures thereof. . The pharmaceutical composition according to claim 4 wherein the organic acid is citric acid or tartaric acid or mixtures thereof. . The pharmaceutical composition according to any of the preceding claims, wherein the weight ratio of the direct thrombin inhibitor to the organic acid is between 0.6 and 8.0, preferably the ratio is between 1.0 and 5.0. . The pharmaceutical composition according to claim 6, wherein the weight ratio of the dabigatran etexilate to the citric acid is between 0.6 and 8.0, preferably the ratio is between 1.0 and 5.0. The pharmaceutical composition according to claim 6, wherein the weight ratio of the dabigatran etexilate to the tartaric acid is between 0.6 and 8.0, preferably the ratio is between 1.0 and 5.0. The pharmaceutical composition according to any of the preceding claims, wherein the composition is further comprising at least one pharmaceutically acceptable excipient which is selected from fillers, disintegrants, diluents, dispersing agents, binders, components, coloring agents, solvents or mixtures thereof. The pharmaceutical composition according to any of the preceding claims, comprising the first formulation and the second formulation wherein, a) the first formulation comprising 30.0 - 800% by weight of the direct thrombin inhibitor in the form the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof; 5.0 - 500% by weight of diluent; 1.0 - 300% by weight of binder; 0.1 - 30% by weight of glidant; 1.0 - 150% by weight of disintegrant; 0.1 - 50% by weight of Iubricant, and b) the second formulation comprising 10.0 - 500% by weight of organic acid pellets or coated (isolated) organic acid pellets or powder mixture containing organic acid; in percentages by weight based on the total weight of the composition. The pharmaceutical composition according to any of the preceding claims, comprising the first formulation and the second formulation wherein, a) the first formulation comprising 30.0 - 800% by weight of the direct thrombin inhibitor in the form the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof; 10.0 - 500% by weight of diluent; 10.0 - 300% by weight of binder; 0.5 - 30% by weight of glidant; 1.0 - 150% by weight of disintegrant; 0.1 - 50% by weight of Iubricant, and b) the second formulation comprising 10.0 - 500% by weight of organic acid pellets or coated (isolated) organic acid pellets or powder mixture containing organic acid; in percentages by weight based on the total weight of the composition. 12. The pharmaceutical composition according to any of the preceding claims, comprising the first formulation and the second formulation wherein, a) the first formulation comprising 10.0 - 500% by weight of organic acid pellets or coated (isolated) organic acid pellets or powder mixture containing organic acid, and b) the second formulation comprising 30.0 - 800% by weight of the direct thrombin inhibitor in the form the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof; 5.0 - 500% by weight of diluent; 1.0 - 300% by weight of binder; 0.1 - 30% by weight of glidant; 1.0 - 150% by weight of disintegrant; 0.1 - 50% by weight of Iubricant; in percentages by weight based on the total weight of the composition. 13. The pharmaceutical composition according to any of the preceding claims, comprising the first formulation and the second formulation wherein, a) the first formulation comprising 10.0 - 500% by weight of organic acid pellets or coated (isolated) organic acid pellets or powder mixture containing organic acid, and b) the second formulation comprising 30.0 - 800% by weight of the direct thrombin inhibitor in the form the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof; 10.0 - 500% by weight of diluent; 10.0 - 300% by weight of binder; 0.5 - 30% by weight of glidant; 1.0 - 150% by weight of disintegrant; 0.1 - 50% by weight of lubricant; in percentages by weight based on the total weight of the composition. 14. The pharmaceutical composition according to claim 10, comprising the first formulation and the second formulation wherein, a) the first formulation comprising 30.0 - 80% by weight of dabigatran etexilate in the form the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof; 5.0 - 500% by weight of microcrystalline cellulose; 1.0 - 300% by weight of hydroxypropyl methyl cellulose; 0.1 - 30% by weight of colloidal silicon dioxide; 1.0 - 150% by weight of croscarmellose sodium; 0.1 - 50% by weight of magnesium stearate, and b) the second formulation comprising 10.0 - 500% by weight of citric acid or tartaric acid pellets or coated (isolated) citric acid or tartaric acid pellets or powder mixture containing citric acid or tartaric acid; in percentages by weight based on the total weight of the composition. 15. The pharmaceutical composition according to claim 11, comprising the first formulation and the second formulation wherein, a) the first formulation comprising 30.0 - 80% by weight of dabigatran etexilate in the form the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof; 10.0 - 500% by weight of microcrystalline cellulose; 10.0 - 300% by weight of hydroxypropyl methyl cellulose; 0.5 - 30% by weight of colloidal silicon dioxide; 1.0 - 150% by weight of croscarmellose sodium; 0.1 - 50% by weight of magnesium stearate, and b) the second formulation comprising 10.0 - 500% by weight of citric acid or tartaric acid pellets or coated (isolated) citric acid or tartaric acid pellets or powder mixture containing citric acid or tartaric acid; in percentages by weight based on the total weight of the composition. 16. The pharmaceutical composition according to claim 12, comprising the first formulation and the second formulation wherein, a) the first formulation comprising 10.0 - 500% by weight of citric acid or tartaric acid pellets or coated (isolated) citric acid or tartaric acid pellets or powder mixture containing citric acid or tartaric acid, b) the second formulation comprising 30.0 - 800% by weight of dabigatran etexilate in the form the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof; 5.0 - 500% by weight of microcrystalline cellulose; 1.0 - 300% by weight of hydroxypropyl methyl cellulose; 0.1 - 30% by weight of colloidal silicon dioxide; 1.0 - 150% by weight of croscarmellose sodium; 0.1 - 50% by weight of magnesium stearate; in percentages by weight based on the total weight of the composition. 17. The pharmaceutical composition according to claim 13, comprising the first formulation and the second formulation wherein, a) the first formulation comprising 10.0 - 500% by weight of citric acid or tartaric acid pellets or coated (isolated) citric acid or tartaric acid pellets or powder mixture containing citric acid or tartaric acid, b) the second formulation comprising 30.0 - 800% by weight of dabigatran etexilate in the form the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof; 10.0 - 500% by weight of microcrystalline cellulose; 10.0 - 300% by weight of hydroxypropyl methyl cellulose; 0.5 - 30% by weight of colloidal silicon dioxide; 1.0 - 150% by weight of croscarmellose sodium; 0.1 - 50% by weight of magnesium stearate; in percentages by weight based on the total weight of the composition. 18. A process for preparation of the pharmaceutical composition according to any preceding claims, wherein the process comprising the following steps: a. Preparing the first formulation in the form of mini tablets or granules or pellets or powder or beads or capsules or mixtures thereof; b. Preparing the second formulation in the form of mini tablets or granules or pellets or powder or beads or capsules or mixtures thereof; c. Filling the second formulation into the second capsule and; d. lnserting the second capsule into the first capsule and subsequently filling the first formulation into the first capsule. 19. The process for preparation of the pharmaceutical composition according to claim 18, wherein the process for the first formulation or the second formulation comprising the following steps: a. Blending dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof and at least one pharmaceutically acceptable excipient; b. Granulating the blend of step (a); 0. Drying or cooling the granules obtained in step (b); d. Optionally adding at least one pharmaceutically acceptable excipient to the granules obtained in step (c) and mixing; e. Filling the mixture into the first capsule or the second capsule. 20. The process for preparation of the pharmaceutical composition according to claim 18, wherein the process for the first formulation or the second formulation comprising the following steps: a. Blending organic acid and optionally at least one pharmaceutically acceptable excipient; b. Granulating the blend of step (a) to form organic acid granules or extruding or spheronizing the blend of step (a) to form organic acid pellets; c. Optionally coating the organic acid granules or pellets with an isolation solution; d. Filling the organic acid granules or pellets obtained in step (b) or step (c) into the first capsule or the second capsule. 21. The process for preparation of the pharmaceutical composition according to claim 14, 15 or 18, wherein the process comprising the following steps: a. Preparing the first formulation comprising i. Blending dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium; ii. Granulating the blend of step (i) with water; iii. Drying the granules obtained in step (ii); iv.OptionaIly adding magnesium stearate to the granules obtained in step (iii) and mixing; b. Preparing the second formulation comprising i. Blending citric acid or tartaric acid with microcrystalline cellulose and solution of hydroxypropyl cellulose in isopropyl alcohol; ii. Extruding or spheronizing the blend of step (i) to form citric acid pellets or tartaric acid pellets; iii. Optionally coating the citric acid pellets or tartaric acid pellets with an isolation solution; c. Filling the second formulation into the second capsule and; d. Inserting the second capsule into the first capsule and subsequently filling the first formulation into the first capsule. 22. The process for preparation of the pharmaceutical composition according to claim 16, 17 or 18, wherein the process comprising the following steps: a. Preparing the first formulation comprising i. Blending citric acid or tartaric acid with microcrystalline cellulose and solution of hydroxypropyl cellulose in isopropyl alcohol; ii. Extruding or spheronizing the blend of step (i) to form citric acid pellets or tartaric acid pellets; iii. Optionally coating the citric acid pellets or tartaric acid pellets with an isolation solution; b. Preparing the second formulation comprising i. Blending dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof, microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and croscarmellose sodium; ii. Granulating the blend of step (i) with water; iii. Drying the granules obtained in step (ii); iv.OptionaIIy adding magnesium stearate to the granules obtained in step (iii) and mixing; c. Filling the second formulation into the second capsule and; d. Inserting the second capsule into the first capsule and subsequently filling the first formulation into the first capsule.
TR2018/06309A 2017-05-10 2018-05-04 Solid oral pharmaceutical compositions of dabigatran etexilate TR201806309A2 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EA201992644A EA201992644A1 (en) 2017-05-10 2018-05-10 SOLID PHARMACEUTICAL COMPOSITIONS BASED ON DABIGATRAN ETHEXILATE FOR ORAL USE
BR112019023781-0A BR112019023781A2 (en) 2017-05-10 2018-05-10 PHARMACEUTICAL COMPOSITION IN A DOSAGE UNIT FORM AND PROCESS FOR PREPARING THE PHARMACEUTICAL COMPOSITION
EP18811675.0A EP3634388A2 (en) 2017-05-10 2018-05-10 Solid oral pharmaceutical compositions of dabigatran etexilate
NZ759901A NZ759901A (en) 2017-05-10 2018-05-10 Solid oral pharmaceutical compositions of dabigatran etexilate
AU2018293361A AU2018293361B2 (en) 2017-05-10 2018-05-10 Solid oral pharmaceutical compositions of dabigatran etexilate
PCT/TR2018/050221 WO2019004980A2 (en) 2017-05-10 2018-05-10 Solid oral pharmaceutical compositions of dabigatran etexilate
EP19848668.0A EP3787624A4 (en) 2018-05-04 2019-05-03 DABIGATRAN ETEXILATE CAPSULE IN CAPSULE COMPOSITIONS
PCT/TR2019/050292 WO2020032885A2 (en) 2018-05-04 2019-05-03 Capsule-in-capsule compositions of dabigatran etexilate
CONC2019/0013649A CO2019013649A2 (en) 2017-05-10 2019-12-03 Oral Solid Pharmaceutical Compositions of Dabigatran Etexilate

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
TR2017/06848A TR201706848A2 (en) 2017-05-10 2017-05-10 SOLID ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING DABIGATRAN ETEXCLATE

Publications (1)

Publication Number Publication Date
TR201806309A2 true TR201806309A2 (en) 2018-11-21

Family

ID=64559741

Family Applications (2)

Application Number Title Priority Date Filing Date
TR2017/06848A TR201706848A2 (en) 2017-05-10 2017-05-10 SOLID ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING DABIGATRAN ETEXCLATE
TR2018/06309A TR201806309A2 (en) 2017-05-10 2018-05-04 Solid oral pharmaceutical compositions of dabigatran etexilate

Family Applications Before (1)

Application Number Title Priority Date Filing Date
TR2017/06848A TR201706848A2 (en) 2017-05-10 2017-05-10 SOLID ORAL PHARMACEUTICAL COMPOSITIONS CONTAINING DABIGATRAN ETEXCLATE

Country Status (8)

Country Link
EP (2) EP3621599A2 (en)
AU (1) AU2018293361B2 (en)
BR (1) BR112019023781A2 (en)
CO (1) CO2019013649A2 (en)
EA (1) EA201992644A1 (en)
NZ (1) NZ759901A (en)
TR (2) TR201706848A2 (en)
WO (1) WO2019004979A2 (en)

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE121699A1 (en) 1997-02-18 1999-12-08 Boehringer Ingelheim Pharma BICYCLE HETERO CYCLES DISSTITUTED AS INHIBITORS OF THROMBIN
DE10337697A1 (en) 2003-08-16 2005-03-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tablet containing 3 - [(2 - {[4- (hexyloxycarbonylamino-iminomethyl) -phenyl-amino] -methyl} -1-methyl-1H-benzimidazole-5-carbonyl) -pyridin-2-yl-amino] - propionic acid ethyl ester or its salts
EA022969B1 (en) 2010-07-01 2016-03-31 Крка, Товарна Здравил, Д.Д., Ново Место Pharmaceutical oral dosage forms comprising dabigatran etexilate and its pharmaceutically acceptable salts
EP3858337A3 (en) * 2012-02-21 2021-09-29 Towa Pharmaceutical Europe, S.L. Oral pharmaceutical compositions of dabigatran etexilate
EP2740471B1 (en) 2012-12-07 2015-05-27 Hexal AG Oral pharmaceutical composition comprising dabigatran etexilate
CN104784147B (en) * 2014-01-20 2018-01-23 成都苑东生物制药股份有限公司 A kind of dabigatran etexilate methanesulfonate pharmaceutical capsules composition and preparation method thereof
IN2014MU01042A (en) 2014-03-26 2015-10-02 Cadila Healthcare Ltd
WO2015155297A1 (en) * 2014-04-11 2015-10-15 Sanovel Ilac Sanayi Ve Ticaret A.S. Pharmaceutical combinations of dabigatran and h2-receptor antagonists
CN104095830A (en) * 2014-05-22 2014-10-15 万特制药(海南)有限公司 Preparation method for mesylate dabigatran capsule
CN105560206A (en) * 2014-10-13 2016-05-11 重庆圣华曦药业股份有限公司 Preparation of Pradaxa capsule
IN2015CH01145A (en) * 2015-03-09 2016-09-16
WO2016142821A2 (en) * 2015-03-09 2016-09-15 Alphamed Formulations Pvt. Ltd Compositions containing a thrombin inhibitor

Also Published As

Publication number Publication date
TR201706848A2 (en) 2018-11-21
EP3621599A2 (en) 2020-03-18
CO2019013649A2 (en) 2020-05-15
NZ759901A (en) 2021-12-24
WO2019004979A3 (en) 2019-04-11
WO2019004979A2 (en) 2019-01-03
BR112019023781A2 (en) 2020-06-02
AU2018293361B2 (en) 2021-09-16
AU2018293361A1 (en) 2020-01-02
EP3634388A2 (en) 2020-04-15
EA201992644A1 (en) 2020-04-07

Similar Documents

Publication Publication Date Title
ES2522297T3 (en) A pharmaceutical form that contains two pharmaceutical active ingredients in different physical forms
TWI478712B (en) Pharmaceutical composition for modified release
JP4999466B2 (en) Matrix-type sustained-release preparation containing basic drug or salt thereof and method for producing the same
TWI744224B (en) Solid preparation
CA2635841A1 (en) Stable pharmaceutical formulations of montelukast sodium
BRPI0812064B1 (en) pharmaceutical formulation in the form of agglomerates, tablets, and process for producing a pharmaceutical formulation
US20200078463A1 (en) Composition having improved water solubility and bioavailability
WO2023195955A1 (en) A film coated tablet comprising selexi̇pag and its preparation process
JPWO2008114859A1 (en) Pharmaceutical composition containing pyrazole derivative
ES2417330T3 (en) Pharmaceutical mini-tablets for the sustained release of flecainide acetate
JP5818219B2 (en) Preparation containing 6,7-unsaturated-7-carbamoylmorphinan derivative
EP2572704A1 (en) Orally-Disintegrating Formulations of Vildagliptin
WO2019004980A2 (en) Solid oral pharmaceutical compositions of dabigatran etexilate
TR201806309A2 (en) Solid oral pharmaceutical compositions of dabigatran etexilate
JP2021080191A (en) Pharmaceutical tablets containing nilotinib as active ingredient and production method thereof
EP3787624A2 (en) Capsule-in-capsule compositions of dabigatran etexilate
WO2018122262A1 (en) Bilayer tablet formulations of dabigatran etexilate
JP7058104B2 (en) Pharmaceutical tablets containing aprepitant as an active ingredient
JP7153197B2 (en) Tableted pharmaceutical composition containing nalfurafine
US20100178342A1 (en) Solid Pharmaceutical Preparation
EP3731931B1 (en) Modified release formulations of fesoterodine
WO2018197613A1 (en) Tablet comprising dabigatran etexilate or pharmaceutically acceptable salt thereof and method of producing same
EP3731824B1 (en) Pharmaceutical tablet compositions of dabigatran
WO2023195956A1 (en) A film coated tablet comprising selexi̇pag and at least one filler
WO2025210680A1 (en) Pharmaceutical composition of relugolix tablet