TR201720779A2 - DOUBLE LAYER TABLET FORMULATIONS OF DABIGATRAN ETEXYLATE - Google Patents
DOUBLE LAYER TABLET FORMULATIONS OF DABIGATRAN ETEXYLATE Download PDFInfo
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- TR201720779A2 TR201720779A2 TR2017/20779A TR201720779A TR201720779A2 TR 201720779 A2 TR201720779 A2 TR 201720779A2 TR 2017/20779 A TR2017/20779 A TR 2017/20779A TR 201720779 A TR201720779 A TR 201720779A TR 201720779 A2 TR201720779 A2 TR 201720779A2
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- 229960003850 dabigatran Drugs 0.000 title abstract description 20
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 title abstract description 20
- 239000007916 tablet composition Substances 0.000 title description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000012458 free base Substances 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims description 58
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 claims description 41
- 229960000288 dabigatran etexilate Drugs 0.000 claims description 39
- 150000007524 organic acids Chemical class 0.000 claims description 38
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 36
- 239000008188 pellet Substances 0.000 claims description 34
- 239000003826 tablet Substances 0.000 claims description 33
- 239000007942 layered tablet Substances 0.000 claims description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 22
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 22
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 22
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 21
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 21
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 21
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 21
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 21
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 19
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 19
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 18
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 18
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 18
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 18
- 235000019359 magnesium stearate Nutrition 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
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- 238000002360 preparation method Methods 0.000 claims description 7
- 238000012216 screening Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 5
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 5
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
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- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims description 4
- 238000007873 sieving Methods 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 229940032147 starch Drugs 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 229960001367 tartaric acid Drugs 0.000 claims description 4
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- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 3
- KSEBMYQBYZTDHS-HWKANZROSA-M (E)-Ferulic acid Natural products COC1=CC(\C=C\C([O-])=O)=CC=C1O KSEBMYQBYZTDHS-HWKANZROSA-M 0.000 claims description 2
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
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- DFYRUELUNQRZTB-UHFFFAOYSA-N Acetovanillone Natural products COC1=CC(C(C)=O)=CC=C1O DFYRUELUNQRZTB-UHFFFAOYSA-N 0.000 claims description 2
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- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
Mevcut buluş, dabigatran eteksilat serbest bazını veya dabigatran eteksilatın farmasötik olarak kabul edilebilir tuzlarını ve en az bir farmasötik olarak kabul edilebilir eksipiyan içeren bir farmasötik çift katmanlı tablet ile ilgilidir.The present invention relates to a pharmaceutical bilayer tablet comprising dabigatran etexylate free base or pharmaceutically acceptable salts of dabigatran etexylate and at least one pharmaceutically acceptable excipient.
Description
TARIFNAME DABIGATRAN ETEKSILATIN ÇIFT KATMANLI TABLET FORMÜLASYONLARI Bulusun Alani Mevcut bulus, dabigatran eteksilat serbest bazini veya dabigatran eteksilatin farmasötik olarak kabul edilebilir tuzlarini ve en az bir farmasötik olarak kabul edilebilir eksipiyan içeren bir farmasötik çift katmanli tablet ile ilgilidir. DESCRIPTION DUAL-LAYER TABLET FORMULATIONS OF DABIGATRAN ETEXSILAT Field of Invention The present invention uses dabigatran etexilate free base or dabigatran etexilate pharmaceutical salts and at least one pharmaceutically acceptable excipient. relates to a pharmaceutical bilayer tablet.
Teknigin Bilinen Durumu Yeni bir direkt trombin inhibitörü olan dabigatran eteksilat, dabigatranin ön ilaci ve peptit olmayan trombin inhibitörüdür. Bu molekül Boehringer Ingelheim ilaç sirketi tarafindan gelistirilmistir. Oral ilaç, gastrointestinal kanaldan emilir ve direkt antikoagülan aktiviteye sahip olan dabigatrana dönüsür. Dabigatran, fibrinojenin fibrine bölünmesini önleyerek ve koagülasyon kaskad agindaki son adimlari ve trombozu bloke ederek, trombinin spesifik fibrin baglama bölgelerine baglanir. Dabigatran, bir fibrin-trombin kompleksinden ayrilabilir ve reversibl antikoagülan etki sergileyebilir. State of the Art Dabigatran etexilate, a new direct thrombin inhibitor, is a prodrug of dabigatran and a peptide It is a non-thrombin inhibitor. This molecule was produced by the pharmaceutical company Boehringer Ingelheim. developed. Oral drug is absorbed from the gastrointestinal tract and has direct anticoagulant activity. the possessor becomes dabigatran. Dabigatran inhibits the cleavage of fibrinogen to fibrin and by blocking the last steps in the coagulation cascade network and thrombosis, binds to fibrin binding sites. Dabigatran can be dissociated from a fibrin-thrombin complex and May exhibit reversible anticoagulant effects.
Dabigatran eteksilatin kimyasal adi 3-[(2-{[4-(hekziIoksikarbonilamino-imino-metiI)-feni- Formül 1'de gösterilmektedir: Dabigatran eteksilat, ABD Gida ve Ilaç Idaresi (FDA) tarafindan non-valvüler atriyal fibrilasyonlu hastalarda inme ve sistemik embolizm riskinin azaltilmasi için onaylanmistir. Dabigatran etexylatin chemical name 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenyl- It is shown in formula 1: Dabigatran etexilate is approved by the US Food and Drug Administration (FDA) for non-valvular atrial It is approved to reduce the risk of stroke and systemic embolism in patients with fibrillation.
Halihazirda onaylanan dozaj formu, 75 mg, 110 mg ve 150 mg'lik yitiliklerdeki kapsüllerdir ve ürün adi Pradaxa'dir. EP 1870100 numarali patent basvurusunda dabigatran eteksilat metansülfonatin pellet formülasyonu açiklanmaktadir. Bu kompozisyon, bir organik asitten ve çekirdegi saran bir aktif katmandan olusan bir çekirdek materyal ile formüle edilmektedir. Her PRADAXA® kapsülü, su yardimci maddeleri içermektedir: akasya zamki, dimetikon, hipromelloz, hidroksipropilselüloz, tartarik asit, karrageenan, potasyum klorür, talk, titanyum dioksit ve jelatin. Önceki teknikte, formülasyonlarin çogu kapsül ve tablet formundadir. Bununla birlikte, teknikteki formülasyonlarin birçogu, ilacin üretim maliyetini artirabilecek veya ilacin hatali veya yanlis uygulanmasina yol açarak islev bozuklugunun görülebilecegi karmasik tekniklerle formüle edilmektedir. The currently approved dosage form is capsules in strengths of 75 mg, 110 mg and 150 mg and The product name is Pradaxa. Dabigatran etexilate in patent application EP 1870100 The methanesulfonate pellet formulation is described. This composition is made of an organic acid and It is formulated with a core material consisting of an active layer surrounding the core. Each The PRADAXA® capsule contains water excipients: gum acacia, dimethicone, hypromellose, hydroxypropylcellulose, tartaric acid, carrageenan, potassium chloride, talc, titanium dioxide and gelatin. In the prior art, most formulations are in capsule and tablet form. With this, Many of the formulations in the art can increase the production cost of the drug or cause the drug to be faulty. complex, where dysfunction may occur, leading to formulated using techniques.
Dabigatran eteksilatin sudaki çözünürlügü yalnizca 1.2 mg/ml'dir. Ek olarak, etkin madde, asidik ortamda büyük ölçüde artan kuvvetli pH'ye bagimli bir çözünürlük sergiler. Etkin maddenin çözünürlügü hastanin midesindeki pH degerine bagli oldugundan, bu durum, konvansiyonel oral farmasötik formülasyonlarin biyoyararlaniminda büyük varyasyonlar olmasina yol açar. Bu, mide pH degerinin fizyolojik degiskenligi, hastalik veya ön tedavilerle (örnegin, proton pompasi inhibitörleri) degisebildigi hastalar için özellikle sorun teskil etmektedir. Dolayisiyla, dabigatran eteksilat içeren gelistirilmis oral farmasötik formülasyonlara hala ihtiyaç duyulmaktadir. The solubility of dabigatran etexilat in water is only 1.2 mg/ml. In addition, the active ingredient exhibits a strong pH-dependent solubility, which increases greatly in acidic media. Effective Since the solubility of the substance depends on the pH value in the stomach of the patient, this is Large variations in bioavailability of conventional oral pharmaceutical formulations causes it to happen. This may be due to physiological variability of gastric pH, disease or pretreatment. (for example, proton pump inhibitors) is particularly problematic for patients whose is doing. Therefore, an improved oral pharmaceutical containing dabigatran etexilate formulations are still needed.
Bu bulusta organik asit, midenin pH degerinden bagimsiz bir salim sunulmasi ve dolayisiyla etkin madde çözünürlügünün ve biyoyararlanimin saglanmasi için kullanilmaktadir. In this invention, organic acid presents a release independent of the pH value of the stomach and thus It is used to provide active substance solubility and bioavailability.
Dabigatran eteksilat, asit ile kombine edildiginde geçimsizlik ve stabilite problemlerine neden olur. Organik asidi dabigatran eteksilat formülasyonundan ayirmanin kolay bir yolunu bulduk. Dabigatran etexilate causes incompatibility and stability problems when combined with acid. It is possible. We found an easy way to separate the organic acid from the dabigatran etexilate formulation.
Bu problemler çok katmanli tablet kullanilarak asildi. Bu sayede, ayni zamanda dissolüsyon profili de iyilesti. Böylece organik asit ile dabigatran eteksilat birbirleriyle etkilesime girmez ve ayrica bu tabletin üretimi kolay ve uygun maliyetli olur. These problems were overcome by using a multilayer tablet. In this way, dissolution profile has also improved. Thus, organic acid and dabigatran etexilate do not interact with each other and furthermore, this tablet is easy and cost-effective to manufacture.
Ek olarak, bu bulusta, her bir katman için uygun eksipiyanlarin seçilmesi ve bunlarin belirli miktarlarda kullanilmasi, yan etki olusturmadan tabletin iyi çözünürlük saglamasi için önemlidir. In addition, in this invention, the selection of suitable excipients for each layer and their specific It should be used in large amounts to ensure good solubility of the tablet without causing side effects. is important.
Bulusun Ayrintili Açiklamasi Mevcut bulusun esas amaci, özellikle çift katmanli tablet olmak üzere çok katmanli tablet kullanarak etkin madde ile asit arasindaki geçimsizlik ve stabilite problemlerinin önüne geçmek ve söz konusu farmasötik formülasyonun hazirlanmasi için kolay ve uygun maliyetli bir proses sunmaktir. Detailed Description of the Invention The main object of the present invention is multilayer tablet, especially double layer tablet. It prevents incompatibility and stability problems between the active substance and the acid by using easy and cost-effective to pass and prepare the pharmaceutical formulation in question. presenting a process.
Mevcut bulusun bir baska amaci, eksipiyanlarin belirli bir oranda seçilmesiyle tablette istenen dissolüsyon profili, istenen biyoyararlanim ve uzun bir raf ömrünün saglanmasidir. It is another object of the present invention that the excipients are selected in a certain ratio and desired in the tablet. The dissolution profile is to ensure the desired bioavailability and a long shelf life.
Etkin maddeler, bazik bir ortama sahip olan ince bagirsagin genis yüzey alani ve yavas peristaltik hareketlerinden dolayi genellikle ince bagirsaktan emilir. Bununla birlikte, asidik bir ortama sahip olan mideden emilim ise midenin hizli peristaltik hareketlerinden ve yüksek yüzey alanindan dolayi ihmal edilebilir derecede düsüktür. Böylece, etkin maddelerin bazik bir ortama sahip olan ince bagirsakta dissolüsyonu önemlidir. Zayif bazik bir madde olan dabigatran, asidik ortamlarda çözünmelidir ve dabigatranin dissolüsyonu çevrenin pH degerine bagimsiz olmalidir. Bu problemler, tablete organik asit veya inorganik asit eklenerek çözülebilir. The active ingredients are the large surface area of the small intestine, which has a basic environment, and the slow Due to its peristaltic movements, it is usually absorbed from the small intestine. However, an acidic Absorption from the stomach, which has a medium environment, is due to the rapid peristaltic movements of the stomach and high It is negligibly low due to the surface area. Thus, the active ingredients Dissolution is important in the small intestine, which has a medium. a weakly basic substance dabigatran must be soluble in acidic environments and dissolution of dabigatran is at the pH of the environment. should be independent of its value. These problems are caused by organic acid or inorganic acid in the tablet. can be solved by adding
Bulusun bir uygulamasinda, organik asit kullanilir. In one embodiment of the invention, organic acid is used.
Buna uygun olarak, seçilen organik asit, mikro ortamin pH”sini uzun süre boyunca düsük tutarken, tablet veya kapsüllerde çözünmeden kalir ve etkin maddenin çözünürlügünü arttirir. Accordingly, the selected organic acid keeps the pH of the microenvironment low for a long time. While holding, it remains undissolved in tablets or capsules and increases the solubility of the active substance.
Ayrica, organik asit, Iubrikan özelliginden dolayi pelletlerin küre haline getirilmesine yardimci olur ve ince pelletlerin üretilmesine katkida bulunur. Organik asit sayesinde, elde edilen ince pelletlerin yüzey alani artar ve sonuç olarak, formülasyonun içerik tekdüzeligi artar. In addition, organic acid helps to spheroid the pellets due to its lubricant property. and contributes to the production of fine pellets. Thanks to the organic acid, the resulting fine The surface area of the pellets increases and, as a result, the content uniformity of the formulation increases.
Bir uygulamada organik asit, pellet formundadir. In one embodiment, the organic acid is in pellet form.
Bu bulusta, organik asit pelletleri kullanilir. Dolayisiyla, mevcut bulus, dabigatran eteksilat veya dabigatran eteksilatin farmasötik açidan kabul edilebilir bir tuzunu ve organik asit pelletleri içeren bir oral farmasötik formülasyon ile ilgilidir. Çok katmanli tabletler, yeni ilaç dagitim sistemi olarak bilinmektedir. Farkli granüllerin çesitli katmanlar formunda tek tabletlerin içerisinde sikistirilmasina çok katmanli tabletler denir. In this invention, organic acid pellets are used. Therefore, the present invention, dabigatran etexilate or a pharmaceutically acceptable salt of dabigatran etexilate and an organic acid It relates to an oral pharmaceutical formulation comprising pellets. Multilayer tablets are known as the new drug delivery system. Variety of different granules Compressing single tablets in the form of layers is called multi-layered tablets.
Genellikle iki ila üç veya daha fazla APl içeren paralel, berrak, renkli, görsel olarak farkli katmanlardan veya islevsel veya islevsel olmayan plasebo katmanlariyla birlikte API'Ierden olusur. Çok katmanli tablet dozaj formlari, etkin maddeler ile eksipiyanlar arasindaki geçimsizlik problemleri gibi çesitli nedenlerle tasarlanmaktadir. Parallel, clear, colored, visually distinct, usually containing two to three or more API from layers or APIs with functional or non-functional placebo layers occurs. Multilayered tablet dosage forms, the interaction between active ingredients and excipients. It is designed for various reasons such as incompatibility problems.
Dabigatran eteksilat, asit ile kombine edildiginde stabilite problemi gösterir. Bu problemler çok katmanli tablet kullanilarak asilir. Böylece asit ile dabigatran birbirleriyle etkilesime girmez ve bu da kolay ve uygun maliyetli bir proses sunar. Baska bir deyisle, bu problem, bulusun esas amaci altinda daha önce bahsedilen farmasötik bir formülasyondan hazirlanan dabigatran eteksilat içeren birinci katman ve organik asit pelletleri içeren ikinci katmandan olusan çift katmanli bir farmasötik tablet vasitasiyla asilabilir. Dabigatran etexilate exhibits stability problems when combined with acid. these problems suspended using a multi-layer tablet. Thus, acid and dabigatran interact with each other. and this provides an easy and cost-effective process. In other words, this problem for the main purpose of the invention, prepared from a pharmaceutical formulation mentioned earlier from the first layer containing dabigatran etexilate and the second layer containing organic acid pellets. It can be suspended via a double-layered pharmaceutical tablet formed.
Bu bulusta, farmasötik çift katmanli tablet: a. dabigatran eteksilat serbest bazini veya dabigatran eteksilatin farmasötik olarak kabul edilebilir tuzlarini ve en az bir farmasötik olarak kabul edilebilir eksipiyan içeren birinci b. organik asit pelletleri ve en az bir farmasötik olarak kabul edilebilir eksipiyan içeren ikinci katman içermektedir, burada; ikinci katmanin birinci katmana agirlik orani, 0.1 ile 4.0 arasinda, tercihen ikinci katmanin birinci katmana agirlik orani 0.4 ile 2.0 arasindadir. In this invention, the pharmaceutical bilayer tablet: a. dabigatran etexilate free base or dabigatran etexilate pharmaceutically salts and at least one pharmaceutically acceptable excipient. b. organic acid pellets and at least one pharmaceutically acceptable excipient the second layer, wherein; weight ratio of second layer to first layer, 0.1 to 4.0 preferably the weight ratio of the second layer to the first layer is between 0.4 and 2.0.
Ikinci katmanin birinci katmana orani, yan etki olusturmadan istenen stabilite ve istenen dissolüsyon profillerinin saglanmasi için önemlidir. The ratio of the second layer to the first layer provides the desired stability and desired stability without side effects. It is important for providing dissolution profiles.
Bu bulusta, birinci katmanda dabigatran eteksilat serbest bazi veya dabigatran eteksilatin farmasötik olarak kabul edilebilir tuzlarinin miktari, agirlikça %200 ila %700, tercihen %300 ila %50.0'dir ve ikinci katmanda organik asit pelletlerinin miktari agirlikça %200 ila %700, tercihen %300 ila %50.0'dir. In this invention, dabigatran etexilate free base or dabigatran etexilate in the first layer amount of pharmaceutically acceptable salts from 200 to 700%, preferably 300% by weight to 50.0% and the amount of organic acid pellets in the second layer is 200 to 700% by weight, preferably 300 to 50.0%.
Bir baska uygulamada, ikinci katmandaki organik asit pelletlerinin birinci katmandaki dabigatran eteksilat serbest bazina veya dabigatran eteksilatin farmasötik olarak kabul edilebilir tuzlarina agirlik orani, 0.1-10.0, tercihen 0.2-50'tir. In another embodiment, the organic acid pellets in the second layer are dabigatran etexilate free base or dabigatran etexilate pharmaceutically acceptable The weight ratio to the soluble salts is 0.1-10.0, preferably 0.2-50.
Bir baska uygulamada, birinci katmanin, esas olarak, organik asit pelleti içermedigi bir farmasötik formülasyon sunulmaktadir. In another embodiment, the first layer is essentially free of organic acid pellets. pharmaceutical formulation is presented.
Uygun organik asit pelletleri, en az bir karboksilik grup içermektedir. Bunlar sitrik asit, tartarik asit, galik asit, orotik asit, p-kumarik asit, hipürik asit, ferulik asit, vanilik asit, fumarik asit, maleik asit, süksinik asit, malik asit, glutamik asit, aspartik asit, oksalik asit, Iaktik asit, formik asit, asetik asit, propionik asit, kaproik asit, benzoik asit, karbonik asit veya bunlarin karisimlari arasindan seçilmektedir. Suitable organic acid pellets contain at least one carboxylic group. These are citric acid, tartaric acid, gallic acid, orotic acid, p-coumaric acid, hipuric acid, ferulic acid, vanillic acid, fumaric acid, maleic acid, succinic acid, malic acid, glutamic acid, aspartic acid, oxalic acid, lactic acid, formic acid, acetic acid, propionic acid, caproic acid, benzoic acid, carbonic acid or their selected from among the mixtures.
Mevcut bulusun bir uygulamasina göre organik asit tercihen sitrik asit veya tartarik asit veya bunlarin karisimlaridir. According to one embodiment of the present invention, the organic acid is preferably citric acid or tartaric acid or are mixtures of these.
Pellet formülasyonlarinin tekrarlanabilirligi, tek birim dozaj formlarinin tekrarlanabilirliginden çok daha iyidir. Bunlar düsük yüzey alani-hacim oranlari itibariyla film kaplama için uygun sistemlerdir. Ayrica, pellet formülasyonlarinin avantajli özelliklerinden birisi, nem, hava ve isik gibi dis faktörlere karsi iyi direnç göstermeleridir. The repeatability of pellet formulations is greater than the repeatability of single unit dosage forms. it is much better. They are suitable for film coating due to their low surface area-to-volume ratio. are systems. In addition, one of the advantageous features of pellet formulations is moisture, air and They show good resistance to external factors such as light.
Bir uygulamada, organik asit pelletleri, izolasyon çözeltisi ile kaplidir. In one embodiment, the organic acid pellets are covered with the isolation solution.
Bir uygulamaya göre, izolasyon çözeltisi, polimerik veya polimerik olmayan farmasötik olarak kabul edilebilir bir bilesenden veya bunlarin karisimlarindan olusmaktadir. According to one embodiment, the isolation solution may be polymeric or non-polymeric pharmaceutical. It consists of an acceptable component or mixtures thereof.
Mevcut bulusun bir uygulamasina göre, her bir katmandaki farmasötik olarak kabul edilebilir eksipiyan, dagiticilar, Iubrikanlar, glidantlar, baglayicilar, dolgu maddeleri veya bunlarin karisimlari arasindan seçilmektedir. According to one embodiment of the present invention, each layer is pharmaceutically acceptable. excipients, dispersants, lubricants, glidants, binders, fillers or their selected from among the mixtures.
Genel olarak, formülasyonda yer alan eksipiyanlar, etkin maddenin çözünürlügü, emilimi, biyoyararlanimi gibi fiziko-kimyasal ve fiziko-kinetik özellikleri pozitif veya negatif yönde etkileyebilir. Bu nedenle, bir etkin maddeye eslik eden eksipiyanlar, formülasyon gelistirilirken dikkatle ve bilinçli bir sekilde seçilmelidir. Formülasyonlar, etkin madde ile eksipiyanlar arasinda fiziko-kimyasal geçimsizlik göstermemelidir. In general, the excipients in the formulation are related to the solubility, absorption, Physico-chemical and physico-kinetic properties such as bioavailability can be positively or negatively affected. may affect. Therefore, excipients accompanying an active substance should be considered when developing a formulation. should be chosen carefully and consciously. Formulations, active substance and excipients should not show physico-chemical incompatibility between
Bu bulusta, her bir katman en az bir ayni eksipiyan içermektedir. In this invention, each layer contains at least one same excipient.
Mevcut bulusun bir baska avantaji, daha az yan etki görülmesidir. Dabigatran eteksilatin çift katmanli tabletinin üretim prosesi sirasinda her bir katman için ayni eksipiyanin kullanilabilinecegi bulunmustur. Bu ayni zamanda etkili ve kolay bir proses saglanmasina yardimci olmaktadir. Another advantage of the present invention is that less side effects occur. Dabigatran etexilatin double the same excipient for each layer during the production process of the layered tablet. found to be usable. This also ensures an efficient and easy process. is helpful.
Eksipiyanlarin seçimi, raf ömrü boyunca ideal dagilma süresinin elde edilmesinde çok önemlidir. Dagitici formülasyonun sertligine ve agizdaki hissine etki ettiginden, özellikle dagitici seçimi, tablet üretiminde büyük bir rol oynamaktadir. Bu nedenle, uygun bir dagiticinin seçilmesi ve optimal düzeyde kullanilmasi, yüksek dagilim hizinin saglanmasi için kritik önem tasir. The choice of excipients is very important in achieving the ideal dispersion time throughout the shelf life. is important. Especially since the dispersant affects the hardness of the formulation and the feeling in the mouth, Dispenser selection plays a major role in tablet production. Therefore, an appropriate to select the distributor and use it optimally, to ensure high dispersion speed. is of critical importance.
Uygun dagiticilar, kroskarmelloz sodyum, mikrokristalin selüloz, nisasta, sodyum nisasta glikolat, krospovidon (çapraz bagli polivinil pirolidon), povidon, poloksamer, düsük ikameli hidroksipropil selüloz, prejelatinize nisasta, sodyum karboksimetil selüloz, kalsiyum karboksimetil selüloz, karboksimetil selüloz, dokusat sodyum, guar zamki, poliakrilik potasyum, sodyum aljinat, aljinik asit, alginatlar, iyon degistirici reçineler, magnezyum alüminyum silika, sodyum glisin karbonat, sodyum Iauril sülfat veya bunlarin karisimlarini içeren bir gruptan seçilmektedir. Suitable dispersants are croscarmellose sodium, microcrystalline cellulose, starch, sodium starch glycolate, crospovidone (cross-linked polyvinyl pyrrolidone), povidone, poloxamer, low substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacrylic potassium, sodium alginate, alginic acid, alginates, ion exchange resins, magnesium aluminum silica, sodium glycine carbonate, sodium lauryl sulfate or mixtures thereof. selected from a group containing
Mevcut bulusun bir uygulamasina göre, tercihen dagitici kroskarmelloz sodyumdur ve her katmanda kullanilmaktadir. According to one embodiment of the present invention, preferably the dispersant is croscarmellose sodium and each used in the layer.
Mevcut bulusta, kroskarmelloz sodyum miktari, her bir katmanin agirliginca %1.0 ile %15.0 arasindadir. In the present invention, the amount of croscarmellose sodium is 1.0% to 15.0% by weight of each layer. are in between.
Mevcut bulusta, dabigatranin farmasötik çift katmanli tableti dagitici olarak kroskarmelloz sodyum içermektedir ve bu sayede dissolüsyon problemi çözülmekte ve sasirtici sekilde daha iyi dissolüsyon profili elde edilmektedir. In the present invention, the pharmaceutical bilayer tablet of dabigatran uses croscarmellose as a dispersant. contains sodium, thus the dissolution problem is solved and surprisingly better dissolution profile is obtained.
Uygun Iubrikanlar, magnezyum stearat, sodyum stearil fumarat, kalsiyum stearat, çinko stearat, talk, mumlar, borik asit, hidrojenlenmis bitkisel yag, sodyum klorat, magnezyum lauril sülfat, sodyum oleat, sodyum asetat, sodyum benzoat, polietilen glikol, stearik asit, yag asidi, fumarik asit, gliseril palmito sülfat, sodyum Iauril sülfat veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable lubricans, magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, containing fumaric acid, glyceryl palmito sulfate, sodium lauryl sulfate or mixtures thereof selected from the group.
Mevcut bulusun bir uygulamasina göre, tercihen Iubrikan magnezyum stearattir ve her katmanda kullanilmaktadir. According to one embodiment of the present invention, preferably Iubrican is magnesium stearate and each used in the layer.
Mevcut bulusta, lubrikan miktari, her bir katmanin agirliginca %0.1 ile %5.0 arasindadir. In the present invention, the amount of lubricant is between 0.1% and 5.0% by weight of each layer.
Uygun glidantlar, kolloidal silikon dioksit, talk, alüminyum silikat veya bunlarin karisimlarini içeren bir gruptan seçilmektedir. Suitable glidants include colloidal silicon dioxide, talc, aluminum silicate or mixtures thereof. selected from a group containing
Mevcut bulusun bir uygulamasina göre, tercihen glidant kolloidal silikon dioksittir ve her katmanda kullanilmaktadir. According to one embodiment of the present invention, preferably the glidant is colloidal silicon dioxide and each used in the layer.
Mevcut bulusta, glidant miktari, her bir katmanin agirliginca %0.5 ile %3.0 arasindadir. In the present invention, the amount of glidant is between 0.5% and 3.0% by weight of each layer.
Uygun baglayicilar, hidroksipropil metil selüloz, prejelatinize nisasta, povidon, kopovidon, kopolividon, polivinilpirolidon, karnabua mumu, pullulan, polimetakrilat, gliseril behenat, hidroksipropil selüloz, karboksimetil selüloz, metil selüloz, hidroksietil selüloz, sodyum karboksimetil selüloz, karboksimetil selüloz kalsiyum, etil selüloz, mikrokristalin selüloz, polimetakrilatlar, polietilen oksit, polivinil alkol, polikarbofil, polivinil asetat ve kopolimerleri, jelatin, nisasta, ksantan zamki, guar zamki, aljinat, karrageen, kolajen, agar, pektin, hiyalüronik asit, karbomer, selüloz asetat ftalat, hidroksipropil nisasta, hidroksietil metil selüloz, polaksomer, polietilen glikol, sekerler, dogal zamklar, poliakrilamid, alüminyum hidroksit, bentonit, laponit, setostearil alkol, polioksietilen-alkil eterler, polidekstroz veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable binders are hydroxypropyl methyl cellulose, pregelatinized starch, povidone, copovidone, copolyvidone, polyvinylpyrrolidone, carnabua wax, pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, ethyl cellulose, microcrystalline cellulose, polymethacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and its copolymers, gelatin, starch, xanthan gum, guar gum, alginate, carrageen, collagen, agar, pectin, hyaluronic acid, carbomer, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose, polaxomer, polyethylene glycol, sugars, natural gums, polyacrylamide, aluminum hydroxide, bentonite, laponite, cetostearyl alcohol, polyoxyethylene-alkyl ethers, polydextrose or selected from the group containing mixtures of these.
Mevcut bulusun bir uygulamasina göre, tercihen baglayici hidroksipropil metil selülozdur ve Mevcut bulusta, baglayici miktari, her bir katmanin agirliginca %10.0 ile %30.0 arasindadir. According to one embodiment of the present invention, preferably the binder is hydroxypropyl methyl cellulose and In the present invention, the amount of binder is between 10.0% and 30.0% by weight of each layer.
Uygun dolgu maddeleri, mikrokristalin selüloz, Iaktoz, mannitol, spreyle kurutulmus manitol, nisasta, dekstroz, sukroz, fruktoz, maltoz, sorbitol, ksilitol, inositol, kaolin, inorganik tuzlar, kalsiyum tuzlari, polisakkaritler, dikalsiyum fosfat, sodyum klorür, dekstratlar, laktitol, maltodekstrin, sukroz-maltodekstrin karisimi, trehaloz, sodyum karbonat, sodyum bikarbonat, kalsiyum karbonat polioller, dekstroz, maltitol veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable fillers are microcrystalline cellulose, lactose, mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, from the group consisting of calcium carbonate polyols, dextrose, maltitol or mixtures thereof is selected.
Mevcut bulusun bir uygulamasina göre tercihen dolgu maddesi mikrokristalin selülozdur ve Mevcut bulusta, dolgu maddesi miktari, her bir katmanin agirliginca %10.0 ile %50.0 arasindadir. According to one embodiment of the present invention, preferably the filler is microcrystalline cellulose and In the present invention, the amount of filler is between 10.0% and 50.0% by weight of each layer. are in between.
Bulusun bu uygulamasina göre, hesaplama, her bir katman için ayri ayri yüzdeler olarak yapilir. Farmasötik çift katmanli tablet sunlari içermektedir: Birinci katman: Agirlikça %20.0-70.0 dabigatran eteksilat serbest bazi veya dabigatran eteksilatin farmasötik olarak kabul edilebilir tuzlari Agirlikça %10.0-50.0 mikrokristalin selüloz Agirlikça %10.0-30 hidroksipropil metil selüloz Agirlikça %0.5-3.0 kolloidal silikon dioksit Agirlikça %1 .0-15.0 kroskarmelloz sodyum Agirlikça %O.1-5.0 magnezyum stearat Ikinci katman: Agirlikça %20.0-70.0 izole organik asit pelletleri Agirlikça %10.0-50.0 mikrokristalin selüloz Agirlikça %10.0-30 hidroksipropil metil selüloz Agirlikça %O.5-3.0 kolloidal silikon dioksit Agirlikça %1 .O-15.0 kroskarmelloz sodyum Agirlikça %O.1-5.0 magnezyum stearat Tablet, bir granülasyon prosesi ile hazirlanabilir. Yöntemlerin bir özelligi, yas granülasyona dayali olarak asagida verilmektedir ve yas granülasyon, bulusun formülasyonlarinin üretimi için kullanilmaktadir. Uygun granülasyon çözeltileri, saf su, etil alkol, gliserin, sorbitol, polietilen glikol, propilen glikol, izopropil alkol veya bunlarin karisimlarini içeren bir gruptan seçilmekte olup, tercihen granülasyon çözeltisi saf sudur. According to this embodiment of the invention, the calculation is calculated as percentages for each layer separately. makes. Pharmaceutical bilayer tablet contains: First layer: 20.0-70.0% by weight dabigatran etexilate free base or dabigatran etexilate pharmaceutical acceptable salts 10.0-50.0% by weight microcrystalline cellulose 10.0-30% hydroxypropyl methyl cellulose by weight 0.5-3.0% by weight colloidal silicon dioxide 1% by weight .0-15.0% croscarmellose sodium 0.1-5.0% by weight magnesium stearate second layer: 20.0-70.0% by weight of isolated organic acid pellets 10.0-50.0% by weight microcrystalline cellulose 10.0-30% hydroxypropyl methyl cellulose by weight 0.5-3.0% by weight colloidal silicon dioxide 1% by weight .O-15.0 croscarmellose sodium 0.1-5.0% by weight magnesium stearate The tablet can be prepared by a granulation process. A feature of the methods is the wet granulation. and wet granulation, production of formulations of the invention. is used for. Suitable granulation solutions, purified water, ethyl alcohol, glycerin, sorbitol, from a group consisting of polyethylene glycol, propylene glycol, isopropyl alcohol or mixtures thereof. is selected, preferably the granulation solution is pure water.
Mevcut bulusun tüm uygulamalarina göre, stabil, uygun maliyetli, hazirlanmasi kolay bir proses ve dabigatran eteksilatin istenen in vitro salinimi, gelistirilmis dissolüsyon profili ve istenen biyoyararlanimi elde edilmektedir. A stable, cost-effective, easy-to-prepare solution for all applications of the present invention. process and the desired in vitro release of dabigatran etexilate, improved dissolution profile and desired bioavailability is achieved.
Direkt baski yöntemi, tablet üretiminde en kolay yöntem oldugundan, kovansiyonel üretim araç gereçleri kullanabildiginden, kisa bir prosedür oldugundan, nispeten ucuz oldugundan, isil kararsiz ve neme duyarli ilaçlarla yüklenebildiginden ve yüksek dozda üretim yapabildiginden, tablet üretiminde en yaygin olarak kullanilan yöntemdir. Since the direct printing method is the easiest method in tablet production, conventional production because you can use tools, because it is a short procedure, because it is relatively inexpensive, Since it can be loaded with heat-labile and moisture-sensitive drugs and high-dose production It is the most widely used method in tablet production.
Mevcut bulusun bir baska uygulamasina göre tablet, film kaplama ile kaplidir. Film kaplama, kaplama maddeleri içermektedir. According to another embodiment of the present invention, the tablet is coated with a film coating. film coating, Contains coating materials.
Uygun kaplama maddesi, polivinil alkol (PVA), talk, polimetakrilatlar, hidroksipropilmetil selüloz, sodyum Iauril sülfat, gliseril monokaprilokaprat, Iaktoz monohidrat, hidroksipropil selüloz, polietilen glikol (PEG), polivinil alkol-polietilen glikol kopolimerleri, etilselüloz dispersiyonlari, polivinilprolidon, polivinilprolidon-vinil asetat kopolimeri (PVP-VA), tüm Opadry® türleri, pigmentler, boyalar, titanyum dioksit, makrogol, renklendirme maddesi veya bunlarin karisimlari arasindan seçilmektedir. Suitable coating agent, polyvinyl alcohol (PVA), talc, polymethacrylates, hydroxypropylmethyl cellulose, sodium Iauryl sulfate, glyceryl monocaprylocaprate, Iactose monohydrate, hydroxypropyl cellulose, polyethylene glycol (PEG), polyvinyl alcohol-polyethylene glycol copolymers, ethylcellulose dispersions, polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), all Opadry® species, pigments, dyes, titanium dioxide, macrogol, coloring agent or selected from among their mixtures.
Uygun renklendirme maddeleri, ferrik oksit, titanyum dioksit, Gida, Ilaç ve Kozmetik (FD&C) boyalari (FD&C mavi, FD&C yesil, FD&C kirmizi, FD&C sari, FD&C lake), ponceau, indigo Ilaç ve Kozmetik (D&C) mavisi, indigotin FD&C mavi, karmoisin indigotin (indigo Karmin); demir oksitler (örnegin, kirmizi, sari, siyah demir oksit), kinolin sarisi, alev kirmizisi, karmin, karmoisin, günbatimi sarisi veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable coloring agents, ferric oxide, titanium dioxide, Food, Pharmaceuticals and Cosmetics (FD&C) dyes (FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lacquer), ponceau, indigo Pharmaceuticals and Cosmetics (D&C) blue, indigotin FD&C blue, carmoisine indigotine (indigo Carmine); iron oxides (eg, red, yellow, black iron oxide), quinoline yellow, flame red, carmine, carmoisin is selected from the group consisting of sunset yellow or mixtures thereof.
Farmasötik çift katmanli tableti hazirlama prosesi, asagidaki adimlardan olusmaktadir: a. birinci katman - mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit, kroskarmelloz sodyum ve dabigatran eteksilat serbest bazi veya dabigatran eteksilatin farmasötik olarak kabul edilebilir tuzu için tartim yapma, eleme ve sonrasinda bunlari karistirma - toz karisimi suyla granül haline getirme - bu granülü 50-550C sicaklikta vakum firininda kurutma ve eleme - bu karisima magnezyum stearat ekleme ve sonrasinda karistirma b. ikinci katman - mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum için tartim yapma, eleme ve sonrasinda bunlari karistirma - toz karisimi suyla granül haline getirme - bu granülü 50-550C sicaklikta vakum firininda kurutma - izole organik asit pelletlerini karisima ekleme ve karistirma - bu karisima magnezyum stearat ekleme ve sonrasinda karistirma c. Ardindan, katmanlara direkt baski uygulanarak çift katmanli tabletler olusturma Ek olarak, tablet, bir film kaplama ile kaplanabilir. Örnek 1: Çift katmanli tablet Birinci Katman (%) Miktar (a/a) Dabigatran eteksilat serbest bazi veya dabigatran eteksilatin farmasötik olarak kabul edilebilir tuzlari %25.0-60.0 Mikrokristalin selüloz %15.0-40.0 Hidroksipropil metil selüloz %12.0-27.0 Kolloidal silikon dioksit %0.6-2.5 Magnezyum stearat %O.2-4.0 Toplam (Birinci katman) 100 Izole organik asit pelletleri %25.0-60.0 Mikrokristalin selüloz %15.0-40.0 Hidroksipropil metil selüloz %12.0-27.0 Kolloidal silikon dioksit %O.6-2.5 Magnezyum stearat %O.2-4.0 Toplam (Ikinci Katman) 100 Farmasötik çift katmanli tableti hazirlama prosesi, asagidaki adimlardan olusmaktadir: a. birinci katman - mikrokristalin selüloz, hidroksipropil kroskarmelloz sodyum ve dabigatran eteksilat serbest bazi veya dabigatran eteksilatin farmasötik olarak kabul edilebilir tuzu için tartim yapma, eleme ve sonrasinda bunlari karistirma,, - toz karisimi suyla granül haline getirme, - bu granülü 50-55°C sicaklikta vakum firininda kurutma ve eleme, - bu karisima magnezyum stearat ekleme ve sonrasinda karistirma, b. ikinci katman kroskarmelloz sodyum tartim yapma, eleme ve sonrasinda bunlari karistirma mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve - toz karisimi suyla granül haline getirme - bu granülü 50-55°C sicaklikta vakum firininda kurutma - izole organik asit pelletlerini karisima ekleme ve sonrasinda karistirma - bu karisima magnezyum stearat ekleme ve karistirma selüloz, kolloidal silikon dioksit, c. ardindan, katmanlara direkt baski uygulanarak çift katmanli tabletler olusturma, d. opsiyonel olarak, çift katmanli tabletleri, film kaplama ile kaplama Örnek 2: Çift katmanli tablet Birinci Katman (%) Miktar (a/a) Dabigatran eteksilat serbest bazi veya dabigatran eteksilatin farmasötik olarak kabul edilebilir tuzlari %30.0-50.0 Mikrokristalin selüloz %20.0-30.0 Hidroksipropil metil selüloz %15.0-25.0 Kolloidal silikon dioksit %0.7-2.0 Magnezyum stearat %0.2-3.0 Toplam (Birinci katman) 100 Izole organik asit pelletleri %30.0-50.0 Mikrokristalin selüloz %20.0-30.0 Hidroksipropil metil selüloz %15.0-25.0 Kolloidal silikon dioksit %0.7-2.0 Magnezyum stearat %0.2-3.0 Toplam (Ikinci Katman) 100 Farmasötik çift katmanli tableti hazirlama prosesi, asagidaki adimlardan olusmaktadir: a. birinci katman - mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit, kroskarmelloz sodyum ve dabigatran eteksilat serbest bazi veya dabigatran eteksilatin farmasötik olarak kabul edilebilir tuzu için tartim yapma, eleme ve sonrasinda bunlari karistirma - toz karisimi suyla granül haline getirme - bu granulü 50-55°C sicaklikta vakum firininda kurutma ve eleme - karisima magnezyum stearat ekleme ve karistirma b. ikinci katman - mikrokristalin selüloz, hidroksipropil metil selüloz, kolloidal silikon dioksit ve kroskarmelloz sodyum için tartim yapma, eleme ve sonrasinda bunlari karistirma - toz karisimi suyla granül haline getirme - bu granülü 50-550C sicaklikta vakum firininda kurutma - izole organik asit pelletlerini bu karisima ekleme ve karistirma - karisima magnezyum stearat ekleme ve sonrasinda karistirma c. ardindan, katmanlara direkt baski uygulanarak çift katmanli tabletler olusturma d. opsiyonel olarak, çift katmanli tabletleri film kaplama ile kaplama.. The pharmaceutical bilayer tablet preparation process consists of the following steps: a. first layer - microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide, croscarmellose sodium and dabigatran etexilate free base or dabigatran weighing, screening and screening for the pharmaceutically acceptable salt of etexilate don't mix them up afterwards - granulating the powder mix with water - drying and sieving this granule in a vacuum oven at a temperature of 50-550C - adding magnesium stearate to this mixture and then mixing b. second layer - microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and for croscarmellose sodium weighing, sifting and then to mix up - granulating the powder mix with water - drying this granule in a vacuum oven at a temperature of 50-550C - adding and mixing isolated organic acid pellets to the mixture - adding magnesium stearate to this mixture and then mixing c. Then, creating double-layered tablets by applying direct pressure to the layers. In addition, the tablet may be coated with a film coating. Example 1: Double-layer tablet First Layer (%) Amount (m/m) Dabigatran etexilate free base or dabigatran etexilatine pharmaceutical acceptable salts 25.0-60.0% Microcrystalline cellulose 15.0-40.0% Hydroxypropyl methyl cellulose 12.0-27.0% Colloidal silicon dioxide 0.6-2.5% Magnesium stearate O.2-4.0% Total (First tier) 100 Isolated organic acid pellets 25.0-60.0% Microcrystalline cellulose 15.0-40.0% Hydroxypropyl methyl cellulose 12.0-27.0% Colloidal silicon dioxide 0.6-2.5% Magnesium stearate O.2-4.0% Total (Tier Second) 100 The pharmaceutical bilayer tablet preparation process consists of the following steps: a. first layer - microcrystalline cellulose, hydroxypropyl croscarmellose sodium and dabigatran etexilate free base or dabigatran weighing, screening and screening for the pharmaceutically acceptable salt of etexilate don't mix them up afterwards,, - granulating the powder mixture with water, - drying and sieving this granule in a vacuum oven at a temperature of 50-55°C, - adding magnesium stearate to this mixture and then mixing, b. second layer weighing, sifting and then mixing croscarmellose sodium microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and - granulating the powder mix with water - drying this granule in a vacuum oven at a temperature of 50-55°C - adding isolated organic acid pellets to the mixture and then mixing - adding magnesium stearate to this mixture and mixing cellulose, colloidal silicon dioxide, c. then creating double-layered tablets by applying direct pressure to the layers, D. optionally, coating double-layer tablets with film coating Example 2: Double-layer tablet First Tier (%) Amount (w/w) Dabigatran etexilate free base or dabigatran etexilatine pharmaceutical acceptable salts 30.0-50.0% Microcrystalline cellulose 20.0-30.0% Hydroxypropyl methyl cellulose 15.0-25.0% Colloidal silicon dioxide 0.7-2.0% Magnesium stearate 0.2-3.0% Total (First tier) 100 Isolated organic acid pellets 30.0-50.0% Microcrystalline cellulose 20.0-30.0% Hydroxypropyl methyl cellulose 15.0-25.0% Colloidal silicon dioxide 0.7-2.0% Magnesium stearate 0.2-3.0% Total (Tier Second) 100 The pharmaceutical bilayer tablet preparation process consists of the following steps: a. first layer - microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide, croscarmellose sodium and dabigatran etexilate free base or dabigatran weighing, screening and screening for the pharmaceutically acceptable salt of etexilate don't mix them up afterwards - granulating the powder mix with water - drying and sieving this granule in a vacuum oven at a temperature of 50-55°C - adding magnesium stearate to the mixture and mixing b. second layer - microcrystalline cellulose, hydroxypropyl methyl cellulose, colloidal silicon dioxide and for croscarmellose sodium weighing, sifting and then to mix up - granulating the powder mix with water - drying this granule in a vacuum oven at a temperature of 50-550C - adding and mixing isolated organic acid pellets to this mixture - adding magnesium stearate to the mixture and then mixing c. then creating double-layered tablets by applying direct pressure to the layers. D. optionally, coating double-layer tablets with film coating.
Izole Organik Asit Pelletlerinin (Kapli Organik Asit Pelletleri) Hazirlanisi: Izolasyon çözeltisinin hazirlanisi: Formül 1: Saf suya HPMC ve sukroz ilave edilir ve karistirilir. Elde edilen karisima talk eklenir ve karistirilir. 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 is mixed.
Formül 2: Saf suya HPMC ve trietil sitrat ilave edilir ve karistirilir. Elde edilen karisima talk eklenir ve karistirilir. Formula 2: HPMC and triethyl citrate are added to the pure water and mixed. Talc is added to the resulting mixture and is mixed.
Formül 3: Saf suya HPMC ilave edilir ve homojenizatörde karistirilir. Elde edilen karisima talk ve PEG 6000 ilave edilir ve homojenizatörde karistirilir. 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, formül 2 veya formül 3tten seçilen izolasyon çözeltisi ile kaplanir. Organic acid pellets with isolation solution selected from formula 1, formula 2 or formula 3 is covered.
Bulusun hazirlanma süreci basittir ve endüstriyel üretim için uygundur. The preparation process of the invention is simple and suitable for industrial production.
Claims (1)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP17210692.4A EP3342401A1 (en) | 2016-12-28 | 2017-12-27 | Bilayer tablet formulations of dabigatran etexilate |
| PCT/EP2017/084642 WO2018122262A1 (en) | 2016-12-28 | 2017-12-27 | Bilayer tablet formulations of dabigatran etexilate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2016/19828A TR201619828A2 (en) | 2016-12-07 | 2016-12-28 | MULTI LAYERED TABLET COMPOSITIONS OF DABIGATRAN |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TR201720779A2 true TR201720779A2 (en) | 2018-07-23 |
Family
ID=64624791
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TR2017/20779A TR201720779A2 (en) | 2016-12-28 | 2017-12-19 | DOUBLE LAYER TABLET FORMULATIONS OF DABIGATRAN ETEXYLATE |
Country Status (1)
| Country | Link |
|---|---|
| TR (1) | TR201720779A2 (en) |
-
2017
- 2017-12-19 TR TR2017/20779A patent/TR201720779A2/en unknown
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