TR201602035A1 - A novel pharmaceutical composition of vorapaxar and metroprolol - Google Patents

A novel pharmaceutical composition of vorapaxar and metroprolol Download PDF

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TR201602035A1
TR201602035A1 TR2016/02035A TR201602035A TR201602035A1 TR 201602035 A1 TR201602035 A1 TR 201602035A1 TR 2016/02035 A TR2016/02035 A TR 2016/02035A TR 201602035 A TR201602035 A TR 201602035A TR 201602035 A1 TR201602035 A1 TR 201602035A1
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pharmaceutical composition
metoprolol
composition according
tablets
gum
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Ulusoy Bozyel Müge
Zengi̇ner Si̇bel
Öztürk Erki̇n
Türkyilmaz Ali̇
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Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi
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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

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Abstract

The present invention relates to pharmaceutical composition comprising vorapaxar and metroprolol as active agents with at least one pharmaceutically acceptable excipient, wherein at least one of the active agents is in the form of controlled release and their use in the treatment of cardiovascular diseases/disorders.

Description

Tarifname VORAPAKSAR VE METOPROLOLUN YENI BIR FARMASOTIK KOMPOZISYONU Bulusun Alani Mevcut bulus, en az bir farmasötik olarak kabul edilebilir eksipiyan ve etken maddeler olarak vorapaksar ve metoprolol içeren, etken maddelerden en az birinin kontrollü salim formunda oldugu farmasötik kompozisyonlar ve bunlarin kardiyovasküler hastaliklarin/rahatsizliklarin tedavisinde kullanimi ile ilgilidir. specification A NEW PHARMACEUTICAL COMPOSITION OF VORAPAKSAR AND METOPROLOL Field of Invention The present invention relates to at least one pharmaceutically acceptable excipient and active ingredients. in the form of a controlled release of at least one of the active ingredients containing vorapaksar and metoprolol pharmaceutical compositions and their prevention of cardiovascular diseases/ailments related to its use in treatment.

Bulusun arka plani Kardiyovasküler hastalik/rahatsizliklar konjestif kalp yetmezligi, seker hastaligiyla baglantili komplikasyonlar, homosistein, hiperkolesterolemi, ateroskleroz, enflamatuvar kalp hastaligi, valvüler kalp hastaligi, restenoz, hipertansiyon (örnegin pulmoner hipertansiyon, Iabil hipertansiyon, idiyopatik hipertansiyon, düsük reninli hipertansiyon, tuz hassasiyetli hipertansiyon, düsük renin, tuz hassasiyetli hipertansiyon, tromboembolik pulmoner hipertansiyon; hamilelikle uyarilan hipertansiyon, renovasküler hipertansiyon; hipertansiyon kaynakli son asama böbrek hastaligi, kardiyovasküler cerrahi prosedürlerle iliskili hipertansiyon, sol ventrikül hipertrofili hipertansiyon ve benzerleri), diyastolik fonksiyon bozuklugu, koroner arter hastaligi, miyokardiyal enfarktüsler, serebral enfarktüsler, damar sertligi, aterojenez, serebrovasküler hastalik, anjin (kronik, stabil, kararsiz ve variant (prinzmetal) anjin pektoris dahil), anevrizma, iskemik kalp hastaligi, serebral iskemi, miyokardiyal iskemi, tromboz, trombosit kümelenmesi, trombositlerin yapismasi, düz kas hücre proliferasyonu, tibbi cihazlarin kullanimiyla iliskili vasküler ya da vasküler olmayan komplikasyonlar, vasküler ya da vasküler olmayan duvar hasari, periferal vasküler hastalik, perkutan transluminal koroner anjiyografinin ardindan neointimal hiperplazi, vasküler greftleme, koroner arter bypass amelliyati, tromboembolik durumlar, anjiyoplasti sonrasi restenoz, koroner plak enflamasyonu, embolizma, inme, sok, ritim bozuklugu, atrial fibrilasyon ya da atrial çarpinti, trombotik tikanma ve reklüzyon serebrovasküler durumlar ve benzerlerini içeren (ancak bunlarla sinirli olmayan), teknik alanda bilinen herhangi bir kardiyovasküler hastaligi kastetmektedir. background of the invention Cardiovascular disease/ailments associated with congestive heart failure, diabetes complications, homocysteine, hypercholesterolemia, atherosclerosis, inflammatory heart disease, valvular heart disease, restenosis, hypertension (e.g. pulmonary hypertension, Iabil hypertension, idiopathic hypertension, low renin hypertension, salt sensitive hypertension, low renin, salt sensitive hypertension, thromboembolic pulmonary hypertension; pregnancy-induced hypertension, renovascular hypertension; hypertension end-stage renal disease associated with cardiovascular surgical procedures hypertension, hypertension with left ventricular hypertrophy, etc.), diastolic function disorder, coronary artery disease, myocardial infarctions, cerebral infarctions, vascular stiffness, atherogenesis, cerebrovascular disease, angina (chronic, stable, unstable and variant (prinzmetal) including angina pectoris), aneurysm, ischemic heart disease, cerebral ischemia, myocardial ischemia, thrombosis, platelet aggregation, platelet adhesion, smooth muscle cell proliferation, vascular or non-vascular, associated with the use of medical devices complications, vascular or non-vascular wall damage, peripheral vascular disease, Neointimal hyperplasia after percutaneous transluminal coronary angiography, vascular grafting, coronary artery bypass surgery, thromboembolic conditions, post angioplasty restenosis, coronary plaque inflammation, embolism, stroke, shock, arrhythmia, atrial fibrillation or atrial flutter, thrombotic occlusion and retention cerebrovascular conditions and any product known in the art, including (but not limited to) the like refers to cardiovascular disease.

Birçok insan miyokardiyal enfarktüs (kalp krizi), ani kalp durmasi, konjestif kalp yetmezligi, inme, periferal vasküler hastalik ve/veya klodikasyon gibi ciddi ila hayati tehdit eden kardiyovasküler durumlardan sikayetçidir. Bunlar için risk faktörleri çok sayida olup dünyada da oldukça yaygindir. Bu risk faktörleri sigara tüketimini, seker hastaligini, hiperkolesterolemiyi (yüksek serum kolesterolü), hipertansiyonu, anjini, sistemik Iupus eritematozusü, önceden geçirilmis kalp krizlerini ya da inmeleri, hemodiyalizi, homosistein seviyelerini, obeziteyi, hareketsiz yasam tarzini, organ nakli geçirmis olmayi, aterosklerozu ve digerlerini içermektedir. Bu risk faktörlerine sahip hastalarda bir kardiyovasküler olayin meydana gelme riskini etkili bir biçimde azaltacak güvenli ve uygun bir farmasötik kompozisyona ihtiyaç vardir. Many people suffer from myocardial infarction (heart attack), sudden cardiac arrest, congestive heart failure, serious to life-threatening, such as stroke, peripheral vascular disease, and/or claudication suffers from cardiovascular conditions. Risk factors for these are numerous and is also quite common. These risk factors include smoking, diabetes, hypercholesterolemia (high serum cholesterol), hypertension, angina, systemic Iupus erythematosis, previous heart attacks or strokes, hemodialysis, homocysteine levels, obesity, sedentary lifestyle, organ transplant, atherosclerosis and others. A cardiovascular event in patients with these risk factors a safe and suitable pharmaceutical that will effectively reduce the risk of composition is needed.

Kardiyovasküler hastaliklar alaninda bilinen tedavi ve ilaçlar atenolol, metoprolol, nadolol, okspenolol, pindolol, propanolol, timolol gibi beta bloke edicileri, doksazosin, fentolamin, indoramin, fenoksibenzamin, prazosin, terazosin, tolazolin gibi alfa bloke edicileri; karisik alfa ve beta bloke edicileri, örnegin bukindolol, karvedilol ve Iabetalol ve bunun gibi maddeleri içermektedir. Known treatments and drugs in the field of cardiovascular diseases are atenolol, metoprolol, nadolol, beta-blockers such as oxpenolol, pindolol, propanolol, timolol, doxazosin, phentolamine, alpha blockers such as indoramine, phenoxybenzamine, prazosin, terazosin, tolazoline; mixed alpha and beta-blockers such as buquindolol, carvedilol and Iabetalol and the like contains.

Metoprolol (Formül I) bir beta-seçici (kardiyoseçici) adrenoreseptör bloke edici ajandir. Uç tuz formunda mevcut olup bunlar metoprolol tartarat, metoprolol süksinat ve metoprolol fumarattir. Metoprolol hipertansiyon, kalp yetmezligi ve gögüs anjininde kullanilmaktadir. Metoprolol kalbin adrenerjik uyarimini bloke ederek etki etmekte ve bu sekilde kalp dokusunun oksijen talebini azaltmaktadir. Görünüse göre bu, bu maddelerin anjin pektoristeki faydali etkilerini ve miyokardiyal enfarktüsteki kalp koruyucu etkisini açiklamaktadir. Buna ilaveten beta-bloke ediciler atardamar hipertansiyonuna sahip hastalarin büyük bölümünde kan basincini normal seviyelere indirmektedir ki bunun da sebebi muhtemelen kari akisina karsi periferal direnç üzerindeki ilave bir etkidir. Metoprolol (Formula I) is a beta-selective (cardioselective) adrenoreceptor blocking agent. tip salt available in the form of metoprolol tartrate, metoprolol succinate and metoprolol is fumarate. Metoprolol in hypertension, heart failure and chest angina is used. Metoprolol acts by blocking the adrenergic stimulation of the heart and this In this way, it reduces the oxygen demand of the heart tissue. It seems that these substances Its beneficial effects in angina pectoris and its cardioprotective effect in myocardial infarction explains. In addition, beta-blockers have arterial hypertension. reduces blood pressure to normal levels in the majority of patients, which The reason is probably an additive effect on peripheral resistance to snow flow.

Formül l. Metoprolol Teknik alanda kardiyovasküler hastaliklar için bilinen bir diger tedavi ve ilaç ise vorapaksar gibi trombin reseptörü antagonistlerini içermektedir. Trombinin farkli hücre türlerinde çesitli faaliyetlere sahip oldugu bilinmektedir ve trombin reseptbrlerinin insan trombositleri, vasküler düz kas hücreleri, endotelyal hücreler ve fibroblastlar gibi hücre türlerinde bulundugu bilinmektedir. Bu nedenle, ayrica proteazla aktive olan reseptör (PAR) antagonistleri olarak da bilinen trombin reseptör antagonistlerinin, trombotik, enflamatuvar, aterosklerotik ve fibroproliferatif hastaliklar ve bunlarin yani sira trombin ve reseptörünün patalojik bir rol üstlendigi diger hastaliklarin tedavisinde faydali olmasi mümkündür. Trombin reseptörü antagonist bilesikleri, anti-trombotik, anti-trombosit kümelenmesi, antiaterosklerotik, antirestenotik ve/veya anti-koagülan faaliyete sahip olabilir. Bu bilesiklerle tedavi edilen trombozla iliskili hastaliklar tromboz, ateroskleroz, restenoz, hipertansiyon, anjin pektoris, ritim bozuklugu, kalp yetmezligi, miyokardiyal enfarktüs, glomerülonefrit, trombotik ve tromboembolitik inme, periferal vasküler hastaliklar, diger kardiyovasküler hastaliklar, serebral iskemi, enflamatuvar rahatsizliklar ve kanserin yani sira trombin ve reseptörünün patalojik bir rol üstlendigi diger rahatsizliklari içermektedir. Formula I. metoprolol Another treatment and drug known in the art for cardiovascular diseases is vorapaxar. includes thrombin receptor antagonists such as Various types of thrombin in different cell types It is known to have activities of thrombin and thrombin receptors in human platelets, vascular found in cell types such as smooth muscle cells, endothelial cells, and fibroblasts. known. Therefore, they are also known as protease-activated receptor (PAR) antagonists. also known thrombin receptor antagonists, thrombotic, inflammatory, atherosclerotic and fibroproliferative diseases, as well as a pathological role of thrombin and its receptor. It is possible that it may be useful in the treatment of other diseases that it undertakes. thrombin receptor antagonist compounds, anti-thrombotic, anti-platelet aggregation, antiatherosclerotic, may have antirestenotic and/or anti-coagulant activity. treated with these compounds thrombosis-related diseases thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic and thromboembolic stroke, peripheral vascular diseases, other cardiovascular diseases, cerebral ischemia, inflammatory disorders and cancer, as well as thrombin and its receptor includes other disorders in which it assumes a pathological role.

Vorapaksar (Formül Il) PAR-l'in aracilik ettigi trombosit kümelenmesinin, trisiklik himbasinden elde edilen seçici bir inhibitörüdür. Bir tuz formu olan vorapaksar sülfat seklinde mevcuttur. Vorapaksar "miyokardiyal enfarktüs ya da periferal atardamar hastaligi geçmisi olan hastalarda trombotik olaylarin azaltilmasi" amaciyla 2014 yilinda FDA'den onay almistir. 3.3.3( Formül ll. Vorapaksar vorapaksarin bisülfat tuzunu açiklamakta ve bu tuzun en az iki kristalimsi polimorfik forma sahip oldugunu belirtmektedir. US 7,235,567 2. Formun kararsiz oldugunu ve zamanla 1.Vorapaksar (Formula II) PAR-1-mediated platelet aggregation, tricyclic It is a selective inhibitor derived from himbacine. In the form of vorapaxar sulfate, a salt form available. Vorapaksar "history of myocardial infarction or peripheral artery disease" It was approved by the FDA in 2014 with the aim of "reducing thrombotic events in patients with 3.3.3( Formula ll. Vorapaksar describes the vorapaxarin bisulfate salt and that this salt has at least two crystalline polymorphic forms. states that you have it. US 7,235,567 that Form 2 was unstable and over time 1.

Formun kristal yapisina dönüstügünü belirtmektedir. A.B.D. Patent Basvurulari US olarak kabul edilebilir bir tuzunun kapsül kompozisyonlarini, tablet kompozisyonlarini ve uygulayarak PAR-1 reseptörünü antagonize ederek çesitli rahatsizliklarin tedavi edilmesi için ve aspirinin farmasötik kombinasyonlarini açiklamaktadir.It states that the form is transformed into a crystal structure. USA. Patent Applications US capsule compositions, tablet compositions and for the treatment of various ailments by antagonizing the PAR-1 receptor by administering describes pharmaceutical combinations of aspirin and aspirin.

Ancak vorapaksar ve metoprololün kombinasyonunu içeren hiçbir patent basvurusu yoktur.However, there are no patent applications involving the combination of vorapaksar and metoprolol.

Kardiyovasküler hastaliklari'rahatsizliklar için farmasötik olarak kabul edilebilir bir tasiyici içerisinde vorapaksar ve metoprololün bir kombinasyonunun terapötik olarak etkili bir miktarini içeren farmasötik kompozisyonlar gelistirmeye ihtiyaç vardir. A pharmaceutically acceptable carrier for cardiovascular diseases' ailments A therapeutically effective combination of vorapaxar and metoprolol in There is a need to develop pharmaceutical compositions containing the amount of

Ayni terap'otik alanda, hatta ayni endikasyonu tedavi etmek için kullanilan ilaçlarin, önceden en azindan ilave terapötik etkilerin elde edilmesi beklentisiyle kombine edilemeyecegi iyi bilinmektedir. Bilimsel literatür, ayni endikasyonlarin tedavisinde kullanilan farkli sinif bilesiklerin güvenli ve etkili dozaj formlarinda birlestirilemeyecegi, bunun da geçimsiz ilaç kombinasyonlari ile sonuçlanacagina iliskin örneklerle doludur. Bugüne degin vorapaksar ve metoprololün bir kombinasyonunu içeren bir farmasbtik kompozisyon üretilmemistir. Bu etken maddelerin ikisinden birini içeren ilaçlar pratikte bir arada uygulansa dahi, bu durum hastalara birden fazla ilacin uygulanmasini gerektirmekte ve uygulamaya iliskin zorluklara yol açmaktadir. Buna ilaveten, her bir etken maddenin bireysel olarak uygulanmasinin yerine kombinasyon halinde uygulanmasi ve formüle edilmesi sayesinde daha iyi tedavi özellikleri ortaya koyulabilir. Ozellikle kontrollü salimli kompozisyonlar bu tür hastalar için bir alternatif niteliginde olup daha iyi hasta uyuncu saglamaktadir. Drugs used in the same therapeutic area, even to treat the same indication, at least it cannot be combined with the expectation of obtaining additional therapeutic effects. known. Scientific literature, different classes used in the treatment of the same indications that the compounds cannot be combined into safe and effective dosage forms, which means incompatible drug It is full of examples that it will result in combinations of Until today, vorapaksar and A pharmaceutical composition containing a combination of metoprolol has not been produced. This factor Even if drugs containing either substance are administered together in practice, this situation requires the administration of more than one drug to patients and causes difficulties in administration. opens. In addition, instead of applying each active ingredient individually, better therapeutic properties thanks to its application and formulation in combination can be revealed. In particular, controlled-release compositions are an alternative for such patients. and provides better patient compliance.

Mevcut bulusun kompozisyonuna göre, kombinasyon halinde vorapaksar ve metoprololün terapbtik olarak etkili bir miktarini içeren ve yukarida söz edilen sorunlarin üstesinden gelen bir dozaj formunun saglanmasi arzulanmaktadir. Bu molekülleri ayni farmasötik form içerisinde bir araya getirmenin temel zorluklari sunlardir: (a) bu farkli etken maddeler arasinda ve/veya aktif maddeler ve kullanilan eksipiyanlar arasindaki fiziko-kimyasal uyumlulugun garanti edilmesi; ve (b) stabilite 'Özellikleri açisindan bu etken maddeler arasindaki farmasbtik uyumlulugun garanti altina alinmasi. Vorapaksar metoprololle birlestirildiginde bu iki ilaç maddesi birbirleriyle uyumlu bir biçimde salinmali, çözülmeli ve emilmelidir. Kompozisyonun etkililigi açisindan her iki ilaç maddesinin de istenen bir sürede kolayca çözünmesi 'Önemli bir faktördür. According to the composition of the present invention, vorapaksar and metoprolol in combination containing a therapeutically effective amount and overcome the above-mentioned problems It is desirable to provide a dosage form. These molecules in the same pharmaceutical form The main challenges of putting them together in (a) between these different active substances and/or the active substances and excipients used ensuring physico-chemical compatibility between and (b) stability Determination of pharmaceutical compatibility between these active substances in terms of their properties. guarantee. When vorapaksar is combined with metoprolol, these two drug substances must be released, dissolved, and absorbed in concert with each other. The effectiveness of the composition In terms of easy dissolution of both drug substances in a desired time, it is an important factor.

Kontrollü salimli dozaj formlari, minimum yan etkiyle bir ilacin belirli bir sürede sabit bir ilaç seviyesi muhafaza edilmek suretiyle önceden belirlenmis bir hizda salinmasi için tasarlanmistir. Fizyolojik olarak aktif bir ilaci içeren kontrollü salimli bir formülasyon, hemen salimli formülasyonlar ile kiyaslandiginda kan derisimlerinin uzun bir süre ya da terapötik derisimin üzerinde muhafaza edilmesine olanak saglamaktadir. Vorapaksar ve metoprololün kontrollü salimli bir formülasyonunun ortaya koyulmasi ile uygulama sikliginin azaltilmasi, ayni zamanda da ayni veya daha iyi terap'otik etkilerin elde edilmesi, bu sayede de uyuncun iyilestirilmesi saglanabilir. Kontrollü salimli formülasyon, ilacin uygulanmasindan hemen sonra kan plazmasi derisimindeki hizli artisi önleyebilir, bu sebeple de olumsuz yan etkileri azaltma veya elimine etme potansiyeli mevcuttur. Controlled-release dosage forms allow a drug to be fixed over a period of time with minimal side effects. to oscillate at a predetermined rate while maintaining its level. is designed. A controlled-release formulation containing a physiologically active drug blood concentrations over a prolonged or therapeutic period compared to release formulations It allows it to be stored on my skin. Vorapaksar and metoprolol Reducing the frequency of administration by introducing a controlled release formulation, obtaining the same or better therapeutic effects at the same time, thereby improving compliance. improvement can be achieved. The controlled-release formulation is released immediately after drug administration. It can prevent the rapid increase in blood plasma concentration after has the potential to reduce or eliminate

Vorapaksar ve metoprololün oral formülasyonlarinin hazirlanmasi için halihazirda çesitli formülasyonlar ve yöntemler bilinmektedir. Ancak bugüne degin vorapaksar ve metoprololün bir kombinasyonunu içeren kontrollü salimli bir farmas'otik kompozisyon üretilmemistir. Diger yandan, kontrollü salimli formülasyonlar, en yaygin olarak kullanilan kapsül ve tablet gibi oral uygulamaya yönelik geleneksel kati dozaj formlariyla kiyaslandiginda daha iyi hasta uyuncu bakimindan git gide Önem kazanmaktadir. Bunlar özellikle pediatrik ve geriatrik hastalarda ve zihinsel problemli hastalarda kullanilmaktadir. Dolayisiyla, kontrollü salimli kompozisyonlar bu tür hastalar için bir alternatif niteliginde olup, kardiyovasküler hastaliklarin tedavisi gibi uzun dönem farmasötik tedavilerle daha iyi hasta uyuncu saglamaktadir. Various products are currently available for the preparation of oral formulations of vorapaksar and metoprolol. formulations and methods are known. However, to date, vorapaksar and metoprolol have been No controlled release pharmaceutical composition has been produced containing a combination of Other On the other hand, controlled-release formulations are the most commonly used oral formulations such as capsules and tablets. Better patient compliance compared to conventional solid dosage forms for administration It is gaining more and more importance in terms of These are especially in pediatric and geriatric patients and It is used in patients with mental problems. Therefore, controlled-release compositions It is an alternative for such patients, such as the treatment of cardiovascular diseases. provides better patient compliance with long-term pharmaceutical treatments.

Bu sebeple, vorapaksar ve metoprololün oral kontrollü salimli formülasyonlarina ve teknigin bilinen durumuna iliskin yukarida açiklanan problemlerin üstesinden gelen ve bunlara göre ilave avantajlar saglayan bu tür formülasyonun hazirlanmasina yönelik bir prosese olan ihtiyaç artmaktadir. Bu düzenlemelere göre, vorapaksar ve metoprololün yani sira en az bir farmasötik olarak kabul edilebilir eksipiyani içeren kontrollü salimli bir formülasyon ortaya koyulmaktad ir. Therefore, oral controlled-release formulations of vorapaxar and metoprolol and the technique overcome the above-described problems of the known state of to a process for the preparation of such formulation that provides additional advantages. the need is increasing. According to these regulations, besides vorapaksar and metoprolol, at least one a controlled-release formulation containing pharmaceutically acceptable excipients. is being put.

Sonuç olarak, sözü edilen dezavantajlar göz 'Önünde bulunduruldugunda, kardiyovasküler hastalikIar/rahatsizliklara karsi terapötik etkileri olan farmasötik kompozisyonlar alaninda bir yenilige ihtiyaç duyulmaktadir.In conclusion, taking into account the aforementioned disadvantages, cardiovascular a field of pharmaceutical compositions with therapeutic effects against diseases/ailments. innovation is needed.

Bulusun Detayli Açiklamasi Mevcut bulus, en az bir farmas'otik olarak kabul edilebilir eksipiyan ve etken maddeler olarak vorapaksar ve metoprolol içeren, etken maddelerden en az birinin kontrollü salim formunda oldugu farmasötik kompozisyonlar ve bunlarin kardiyovasküler hastalikIarin/rahatsizliklarin tedavisinde kullanimi ile ilgilidir edilmesi ve bu etkinin de söz konusu ilaçlar ayri ayri kullanildiginda elde edilecek etkiden yüksek olmasidir. Diger taraftan mevcut bulusa göre birlestirilecek her bir ilacin düsük dozlarinin kullanilmasi toplam dozaji azaltacaktir. Diger bir deyisle dozajlar azalmayip ilaçlarin verilme sikligi azaltilabilir ve bu da yan etkilerin görülme sikligini azaltmak açisindan faydali olacaktir. Tüm bunlar tedavi edilecek hastalar açisindan avantajli durumlardir.Detailed Description of the Invention The present invention relates to at least one pharmaceutically acceptable excipient and active ingredients. in the form of a controlled release of at least one of the active ingredients containing vorapaksar and metoprolol pharmaceutical compositions and their cardiovascular diseases/ailments related to its use in the treatment and that this effect is less than the effect that will be obtained when the drugs in question are used separately. that is high. On the other hand, each drug to be combined according to the present invention has a low doses will reduce the total dosage. In other words, the dosages do not decrease. The frequency of administration of drugs can be reduced, which can reduce the incidence of side effects. It will be useful. All these are advantageous conditions for the patients to be treated.

Mevcut bulusun bir diger amaci istenen geçimlilik seviyesine sahip bir kombinasyonun elde edilmesidir. It is another object of the present invention to obtain a combination with the desired level of compatibility. is to be done.

Farkli etki mekanizmasina sahip ilaçlar birlestirilebilir. Ancak, farkli etki mekanizmalarina sahip olan ama benzer hedefler üzerinde etki eden bir ilaç kombinasyonun kesinlikle pozitif etkilere sahip olacagini belirtmek mümkündür. Drugs with different mechanisms of action can be combined. However, different mechanisms of action A combination of drugs that have similar targets but act on similar targets is definitely positive. It is possible to state that it will have effects.

Bulusun içerdigi iki aktif bilesen farmas'otik olarak kabul edilebilir bir tasiyici içerisinde vorapaksar ve metoprololü içeren tek bir farmasötik kompozisyon ile uygulanmaktadir. The two active ingredients of the invention are contained in a pharmaceutically acceptable carrier. It is administered with a single pharmaceutical composition containing vorapaksar and metoprolol.

Mevcut bulus, vorapaksar ya da bunun farmasbtik olarak kabul edilebilir bir tuzunu ve metoprolol ya da bunun farmasötik olarak kabul edilebilir bir tuzunu ve en az bir farmasötik olarak kabul edilebilir eksipiyani içeren bir farmasötik kompozisyon ortaya koymakta olup, burada etken maddelerden en az biri kontrollü salim formundadir. yavas salim ya da geciktirilmis salim ya da kademeli salim ya da programli salim anlaminda kullanilmistir. Faz, midede veya ince bagirsakta yavas bir sekilde çözünmesini saglayan bir hiz kontrol edici ajani içermektedir. Bu durumda etken madde yavas bir sekilde çözüneceginden, kan dolasimi içerisine de yavas bir sekilde absorbe edilecektir. Bu yüzden, hiz kontrol edici ajan etken maddenin ç'ozünme hizini veya çözünme profilini etkilemektedir. The present invention describes vorapaksar or a pharmaceutically acceptable salt thereof and metoprolol or a pharmaceutically acceptable salt thereof and at least one pharmaceutical A pharmaceutical composition containing acceptable excipients, wherein at least one of the active ingredients is in the form of controlled release. in the sense of slow release or delayed release or incremental release or programmed release used. Phase is a substance that dissolves slowly in the stomach or small intestine. Contains rate controlling agent. In this case, the active ingredient is slowly Since it will dissolve, it will also be slowly absorbed into the bloodstream. For this reason, The rate controlling agent affects the dissolution rate or dissolution profile of the active ingredient.

Mevcut bulusun bir diger amaci, vorapaksar ve metoprololün kan dolasimindaki salimini, günde bir kez veya iki kez uygulanan doz yetecek sekilde daha uzun bir süre muhafaza etmek suretiyle plazma derisim seviyesini stabil hale getiren, dolayisiyla da hasta uyuncunu arttiran bir farmasötik formülasyon ortaya koymaktir. Another object of the present invention is the release of vorapaksar and metoprolol from the bloodstream, The once or twice daily dose is maintained for a sufficiently long period of time. which stabilizes the plasma skin level, thereby increasing patient compliance. To present a pharmaceutical formulation that increases

Mevcut bulusa göre farmasötik kombinasyonda yer alan etken maddelerin tercih edilen dozlari terap'ötik olarak aktif dozlardir ve özellikle de piyasada satilanlarin dozlarina karsilik gelmektedir. Terapotik olarak aktif miktar sadece terapbtik dozlari degil, ayrica önleyici/profilaktik dozlari da içermektedir. According to the present invention, the preferred choice of active ingredients in the pharmaceutical combination doses are therapeutically active doses, especially in comparison to commercially available doses. is coming. The therapeutically active amount is not only the therapeutic doses, but also It also includes preventive/prophylactic doses.

Bir düzenlemeye göre vorapaksar miktari 0,01 mg ve 50 mg arasinda, tercihen 0,1 mg ve 30 mg arasinda ve daha tercihen 0,5 mg ve 20 mg arasinda bir miktardadir. According to one embodiment, the amount of vorapaxar is between 0.01 mg and 50 mg, preferably between 0.1 mg and 30 mg. mg, and more preferably between 0.5 mg and 20 mg.

Burada kullanildigi sekliyle "vorapaksar" vorapaksar bazi ya da bunun farmasotik olarak kabul edilebilir herhangi bir tuzunu ifade etmektedir. Mevcut bulusun amaci dogrultusunda vorapaksarin farmasötik olarak kabul edilebilir tuzu tercihen vorapaksar sülfattir."vorapaksar" as used herein is vorapaksar base or its pharmaceutical means any acceptable salt. For the purpose of the present invention The pharmaceutically acceptable salt of vorapaxarin is preferably vorapaxar sulfate.

Yukarida listelenen bir hastalik ya da durumun tedavisi için kullanilacak günlük vorapaksar dozu bir kg vücut agirligi için günde yaklasik 0,001 ila yaklasik 100 mgi'kg, tercihen yaklasik 0,001 ila yaklasik 10 mg/kg, örnegin yaklasik 1 mg ila yaklasik 75 mg, özel uygulamaya göre de yaklasik 1 mg ila yaklasik 50 mg'dir (örnegin 2,5 mg). Bu nedenle 70 kiloluk ortalama bir vücut agirligi için dozaj seviyesi günlük ilaç basina (tek bir doz ya da bölünmüs iki doz seklinde uygulanir) yaklasik 0,1 ila yaklasik 700 mg arasindadir. Daily vorapaxar to be used to treat a disease or condition listed above dose is about 0.001 to about 100 mgi'kg per kg of body weight per day, preferably about approx. 0.001 to about 10 mg/kg, eg about 1 mg to about 75 mg, depending on specific application at about 1 mg to about 50 mg (eg 2.5 mg). Therefore, an average of 70 kg dosage level for body weight per drug per day (a single dose or two divided doses) It is administered in the form of approximately 0.1 to approximately 700 mg.

Bir diger düzenlemede mevcut bulusun dozaj formu 2,08 mg vorapaksar baza esdeger 2,5mg vorapaksar sülfat içermektedir. In another embodiment, the dosage form of the present invention is equivalent to 2.08 mg of vorapaksar base. It contains 2.5mg vorapaxar sulfate.

Bir düzenlemeye göre metoprolol miktari 5mg ve 500mg arasinda, tercihen 10mg ve 250mg arasinda ve daha tercihen 15mg ve 220mg arasindadir. According to one embodiment, the amount of metoprolol is between 5mg and 500mg, preferably between 10mg and 250mg and more preferably between 15mg and 220mg.

Burada kullanildigi sekliyle "metoprolol'i terimi bir metoprolol bazi ya da bunun herhangi bir farmasötik olarak kabul edilebilir tuzunu ifade etmektedir. Mevcut bulusun amaci dogrultusunda metoprololün farmasötik olarak kabul edilebilir tuzlari tercihen metoprolol tartarat, metoprolol süksinat ve metoprolol fumarattir. 47,37 mg ve 94,74 mg metoprolol fumarat içermektedir. As used herein, the term "metoprolol" is a metoprolol base or any combination thereof. refers to the pharmaceutically acceptable salt. Purpose of the present invention pharmaceutically acceptable salts of metoprolol, preferably metoprolol tartrate, metoprolol succinate and metoprolol fumarate. It contains 47.37 mg and 94.74 mg metoprolol fumarate.

Farmasötik kompozisyon 0,5 mg ve 20 mg arasinda bir miktarda vorapaksar ve 15 mg ve 220 mg arasinda bir miktarda metoprolol içermektedir. The pharmaceutical composition contains vorapaksar in an amount between 0.5 mg and 20 mg and It contains metoprolol in an amount of 220 mg.

Bir düzenlemeye göre metoprololün vorapaksara orani 1 ila 220 (ala) araliginda, tercihen 1 ila 100 (ala) araliginda ve daha tercihen 2 ila 80 (ai'a) araligindadir. According to one embodiment, the ratio of metoprolol to vorapaxara is in the range of 1 to 220 (ala), preferably 1 to 100 (ai'a) and more preferably 2 to 80 (ai'a).

Bir düzenlemeye göre mevcut bulusta kullanilan oranlar terapi için gereken etkili dozu ve hem vorapaksar ve hem de metoprolol için istenen çözünme profillerini garanti altina almaktadir. According to one embodiment, the ratios used in the present invention include the effective dose required for therapy and ensure the desired dissolution profiles for both vorapaksar and metoprolol. takes.

Mevcut bulusun bir diger amaci, yukarida bahsi geçen tüm dezavantajlari ortadan kaldirmak ve ilgili teknik alana ilave avantajlar kazandirmak üzere, kardiyovasküler hastaliklarin/rahatsizliklarin tedavisinde kullanilmaya yönelik olarak en az bir hiz kontrol edici ajan içerecek sekilde hemen salimli faz ile kontrollü salimli fazi içeren ve vorapaksar ya da bunun farmasötik olarak kabul edilebilir bir tuzu ile metoprolol ya da bunun farmasötik olarak kabul edilebilir bir tuzunun farmasötik formülasyonunu ortaya koymaktir. gelmektedir. Etken maddenin çözünme hizini veya çözünme profilini etkileyen bir eksipiyan mevcut degildir. Another object of the present invention is to eliminate all the above-mentioned disadvantages. and to give additional advantages to the related technical field, cardiovascular At least one rate controller for use in the treatment of diseases/ailments containing an immediate-release phase and a controlled-release phase containing the agent and vorapaxar or metoprolol or a pharmaceutically acceptable salt thereof is to provide a pharmaceutical formulation of an acceptable salt of it. is coming. An excipient that affects the dissolution rate or dissolution profile of the active substance not available.

Bir düzenlemede, vorapaksarin hemen salimli fazini ve metoprololün kontrollü salimli fazini ve bir hiz kontrol edici ajan olan en az bir farmasötik olarak kabul edilebilir eksipiyani içeren farmasötik kompozisyon ortaya koyulmaktadir. In one embodiment, vorapaxarin has an immediate-release phase and a controlled-release phase of metoprolol. and at least one pharmaceutically acceptable excipient which is a rate controlling agent. pharmaceutical composition is disclosed.

Bir düzenlemede, vorapaksarin kontrollü salimli fazini ve metoprololün hemen salimli fazini ve bir hiz kontrol edici ajan olan en az bir farmasötik olarak kabul edilebilir eksipiyani içeren farmasötik kompozisyon ortaya koyulmaktadir. In one embodiment, vorapaxarin has a controlled-release phase and an immediate-release phase of metoprolol. and at least one pharmaceutically acceptable excipient which is a rate controlling agent. pharmaceutical composition is disclosed.

Bir düzenlemede, vorapaksarin kontrollü salimli fazini ve metoprololün kontrollü salimli fazini ve bir hiz kontrol edici ajan olan en az bir farmasötik olarak kabul edilebilir eksipiyani içeren farmasötik kompozisyon ortaya koyulmaktadir. In one embodiment, vorapaxarin produces a controlled-release phase and a controlled-release phase of metoprolol. and at least one pharmaceutically acceptable excipient which is a rate controlling agent. pharmaceutical composition is disclosed.

Bulusun bir düzenlemesinin amaci vorapaksar ve metoprololü istenen çözünme profilleriyle birlikte ayni stabil dozaj formu içerisinde birlestirmektir. The object of one embodiment of the invention is to combine vorapaksar and metoprolol with the desired dissolution profiles. together in the same stable dosage form.

Bu yeni bulusta, farkli fazlardaki etken maddeler, vorapaksar ve metoprololü içeren formülasyonda arzu edilen bir salim elde etmeye olanak saglamaktadir. Ozellikle çözünme hizina bagli olarak tedavi baslangici istenen seviyede elde edilebilir.Bu kompozisyon saglamaktadir. In this new invention, the active ingredients in different phases contain vorapaksar and metoprolol. it allows to obtain a desired release in the formulation. Especially the dissolution Depending on the speed of the treatment initiation can be achieved at the desired level. This composition it provides.

Bir düzenlemeye göre farmasbtik kompozsiyon oral, parenteral, intranazal, dilalti, transdermal, transmukozal, oftalmik, intravenöz, pulmoner, intramasküler ya da rektal yolla uygulanmakta; tercihen de oral yolla uygulanmaktadir. According to one embodiment, the pharmaceutical composition is oral, parenteral, intranasal, sublingual, by transdermal, transmucosal, ophthalmic, intravenous, pulmonary, intramuscular, or rectal route being implemented; preferably orally.

Bulusun bu düzenlemesine göre sözü edilen farmasbtik kompozisyon, oral uygulama için bir dozaj formuna uygun bir biçimde seçilmis uygun farmasötik seyrelticiler, eksipiyanlar ya da tasiyicilarla formüle edilebilir. According to this embodiment of the invention, said pharmaceutical composition is a pharmaceutical composition for oral administration. suitable pharmaceutical diluents, excipients, or can be formulated with carriers.

Bu bulusun bir diger düzenlemesinde farmasötik kompozisyon kati, sivi ya da yari kati dozaj formu seklindedir. In another embodiment of the present invention, the pharmaceutical composition is solid, liquid, or semi-solid dosage. form.

Bulusun bu düzenlemesine göre farmasotik kompozisyon sikistirilmis tabletler, kaplanmis ya da kaplanmamis tabletler, çok tabakali tabletler, mini tabletler, bukkal tabletler, dilalti tabletler, modifiye salim tabletleri, film kapli tabletler, midede dagilan tabletler, pelletler, efervesan kompozisyonlar, haplar, kapsüller, sert jelatin kapsüller, tozlar, kapli boncuk sistemleri, granüller, mikroküreler, iyon degisim reçinesi sistemleri, steril çözeltiler ya da süspansiyonlar, ampüller, parenteral sistemler, kremler, jeller, drajeler, oral yolla uygulanabilir filmler, çüzeltiler, katilar, süspansiyonlar, koloidal dispersiyonlar, emülsiyonlar Bulusun farmas'otik kompozisyonu tercihen pellet ya da tablet ya da Çok tabakali tablet ya da kapsül formundadir. According to this embodiment of the invention, the pharmaceutical composition is compressed tablets, coated or uncoated tablets, multilayer tablets, mini tablets, buccal tablets, sublingual tablets, modified release tablets, film-coated tablets, gastric dispersible tablets, pellets, effervescent compositions, pills, capsules, hard gelatin capsules, powders, coated beads systems, granules, microspheres, ion exchange resin systems, sterile solutions or suspensions, ampoules, parenteral systems, creams, gels, dragees, orally applicable films, solutions, solids, suspensions, colloidal dispersions, emulsions The pharmaceutical composition of the invention is preferably pellet or tablet or Multilayer tablet or in capsule form.

Mevcut bulus, doz bosalmasi önlenecek ve günde bir kez ya da günde iki kez doz yetecek biçimde gerek duyulan kan düzeyleri daha uzun bir süre muhafaza edilecek ve bu sayede de hasta uyuncu arttirilacak sekilde terap'otik fayda saglayan bir hiz kontrol edici ajani iceren, vorapaksarin hemen salimli fazini ve metoprololün kontrollü salimli fazini içeren bir farmasötik kombinasyon ile ilgilidir. The present invention will prevent overdose and once or twice daily dosing will suffice. the blood levels needed will be maintained for a longer period of time, thus containing a rate-controlling agent that provides therapeutic benefit so as to increase patient compliance, A drug containing the immediate-release phase of vorapaxarin and the controlled-release phase of metoprolol. relates to the pharmaceutical combination.

Mevcut bulusun düzenlemesine göre, vorapaksar ve/veya metoprolol kontrollü salim formunda olup bunun ortalama ve günlük tek bir dozdaki in vitro (canli disi) salim profilinde BO'i 8 saatte, %80'i ise en az 20 saatte salinmaktadir. According to the embodiment of the present invention, vorapaksar and/or metoprolol controlled release It is in the form of an in vitro (non-living) release profile that is average and at a single daily dose. BO is released in 8 hours and 80% in at least 20 hours.

Bulusun bir diger düzenlemesine göre vorapaksar ve metoprolol içeren farmasötik kompozisyon günde bir (QD) ya da iki kez (BID), tercihen günde bir kez uygulanmaktadir. According to another embodiment of the invention, pharmaceutical containing vorapaksar and metoprolol the composition is administered once a day (QD) or twice a day (BID), preferably once a day.

Farmasötik kompozisyon insan ya da hayvanlar dahil olmak üzere tedaviye ihtiyaci olan herhangi bir hastaya uygulanir. The pharmaceutical composition is in need of treatment, including humans or animals. applicable to any patient.

Yukarida söz edilen zorluklardan ötürü eksipiyanlarin seçimi çok önemlidir. Bu düzenlemeye göre bir ya da birden fazla farmas'otik olarak kabul edilebilir eksipiyan tamponlama ajanlari, stabilizbrler, antioksidanlar, baglayicilar, seyrelticiler, dagitici ajanlar, hiz kontrol edici ajanlar, renklendiriciler, inert ajanlar, kaplama ajanlari ya da bunlarin karisimlari arasindan seçilmektedir. Because of the difficulties mentioned above, the choice of excipients is very important. to this arrangement one or more pharmaceutically acceptable excipient buffering agents, stabilizers, antioxidants, binders, diluents, dispersing agents, rate controlling agents, colorants, inert agents, coating agents or mixtures thereof. is selected.

Uygun tamponlayici ajanlar alkali metal sitrat, sitrik asit/sodyum sitrat, tartarik asit, fumarik asit, sorbik asit, sitrik asit, süksinik asit, adipik asit, askorbik asit, glutarik asit, potasyum hidrojen tartarat, sodyum hidrojen tartarat, potasyum hidrojen fitalat, sodyum hidrojen fitalat, potasyum dihidrojen fosfat, sodyum dihidrojen fosfat, disodyum hidrojen fosfat, hidroklorik asit/sodyum hidroksit ya da bunlarin karisimlari ve tercihen sitrik asit, fumarik asit, askorbik asit, sodyum dihidrojen fosfat, glisin, glutamik asit ya da bunlarin karisimlari arasindan seçilebilmekle birlikte sadece bunlarla sinirli degildir.Suitable buffering agents are alkali metal citrate, citric acid/sodium citrate, tartaric acid, fumaric acid, sorbic acid, citric acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, hydrochloric acid/sodium hydroxide or mixtures thereof, preferably citric acid, fumaric acid, ascorbic acid acid, sodium dihydrogen phosphate, glycine, glutamic acid or mixtures thereof. can be selected, but not limited to these only.

Uygun stabilizörler sitrik asit, fumarik asit, tartarik asit, sodyum sitrat, sodyum benzoat, sodyum dihidrojen fosfat, kalsiyum karbonat, magnezyum karbonat, arjinin, Iizin, meglamin, askorbik asit, gallik asit esterler ya da bunlarin karisimlari ve tercihen sitrik asit, fumarik asit, arjinin ya da bunlarin karisimlari arasindan seçilebilmekle birlikte sadece bunlarla sinirli degildir. Suitable stabilizers are citric acid, fumaric acid, tartaric acid, sodium citrate, sodium benzoate, sodium dihydrogen phosphate, calcium carbonate, magnesium carbonate, arginine, Iizin, meglamine, ascorbic acid, gallic acid esters or mixtures thereof, preferably citric acid, fumaric acid, Can be selected from arginine or mixtures thereof, but limited to these is not.

Uygun antioksidanlar alfa tokoferol, askorbik asit, askorbil palmitat, bütilhidroksianizol (BHA), bütilhidroksitoluen (BHT), eritorbik asit, monotiyogliserol, potasyum metabisülfit, propil gallat, sodyum askorbat, sodyum metabisülfit, sodyum sülfit, timol ya da bunlarin karisimlari arasindan seçilebilmekle birlikte bunlarla sinirli degildir. Suitable antioxidants are alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), erythorbic acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium ascorbate, sodium metabisulfite, sodium sulfite, thymol or mixtures thereof Although you can choose from among them, it is not limited to them.

Uygun baglayicilar polivinilpirolidon, polietilen glikol, polivinil alkol, nisasta, prejelatinize nisasta, glikoz, glikoz surubu, dogal sakizlar, sukroz, sodyum aljinat, hidroksipropil metil selüloz, hidroksipropil sel'uioz, karboksi metil selüloz, metil seIL'iIoz gibi selüloz türevleri, jelatin, karajenan, guar sakizi, karbomer, polimetakrilatlar, metakrilat polimerler, kolajenler, jelatin benzeri proteinler, agar, aljinat, aljinik asit, ksantan sakizi, hiyalüronik asit, pektin, polisakkaritler, karbomer, poloksamer, poliakrilamit, aluminyum hidroksit, Iaponit, bentonit, polioksietilen-alkil eter, polidekstroz, polietilen oksit ya da bunlarin karisimlari arasindan seçilebilmekle birlikte sadece bunlarla sinirli degildir. Suitable binders are polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, starch, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, hydroxypropyl methyl cellulose derivatives such as cellulose, hydroxypropyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, collagens, gelatin-like proteins, agar, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, Iaponite, bentonite, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof. can be selected, but not limited to these only.

Uygun seyrelticiler mikrokristalin seluloz, mannitol, püskürti'ilerek kurutulmus mannitol, kaolin, inorganik tuzlar, kalsiyum tuzlari, polisakkaritler, dikalsiyum fosfat, sodyum klor'ur, dekstratlar, Iaktitol, maltodekstrin, sukroz-maltodekstrin karisimi, trehaloz, sodyum karbonat, sodyum bikarbonat, kalsiyum karbonat ya da bunlarin karisimlari arasindan seçilebilmekle birlikte sadece bunlarla sinirli degildir. Suitable diluents are microcrystalline cellulose, mannitol, spray-dried mannitol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, Iactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, can be chosen from sodium bicarbonate, calcium carbonate or mixtures thereof. together, it's not just limited to them.

Uygun dagitici ajanlar kalsiyum silikat, magnezyum aluminyum silikat ya da bunlarin karisimlari arasindan seçilebilmektedir. Suitable dispersing agents are calcium silicate, magnesium aluminum silicate or their can be selected among the mixtures.

Uygun hiz kontrol edici ajanlar etil akrilat, etil metakrilat kopolimer, etilsel'uloz, metilsel'uloz, hipromelloz fitalat, polidekstroz, polivinilasetat fitalat, zein, polivinilpirolidon, polivinil alkol, polivinil asetat, hidroksipropil selüloz, hidroksipropil metilselüloz, hidroksipropil metilseI'L'iloz E4M, hidroksipropil metilselt'iloz K100MCR, hidroksietil selüloz, hidroksimetil selüloz, jelatin, polietilen oksit, akasya, dekstrin, nisasta, polihidroksietilmetakrilat, sodyum karboksimetilselüloz, karboksimetil selüloz, sodyum aljinat, aljinik asit, pektin, poliglukoronik asit, poligalakturonik asit, kondroitik sülfate, karajenan, Iambda karajenan, iota karajenan, fursellaran, ksantan sakizi, bir akrilik asit polimeri, karbopol, agar, guar sakizi, pisilyum sakizi, gellan sakizi, keçi boynuzu sakizi, tara sakizi, tamarind sakizi, arap sakizi, kurdlan, galaktomannan, glukomannan, nitroselüloz, metilselüloz, proteoglikan, glikoprotein, aktin, tubulin, hemoglobin, insülin, fibrin, albumin, miyosin, kolajen, kazein, pullulan, kitozan, gliserol, propilen glikol, makrogoller, fitalat esterleri, dibutil sebasetat, sitrat esterleri, triasetin, hint yagi, asetillenmis monogliseridler, parçalara ayrilmis hindistan cevizi yagi, hidrojenlenmis bitkisel yag, hidrojenlenmis hint yagi, karnauba mumu, kandellia mumu, balmumu, parafin mumu, stearik asit, gliseril behenat, setil alkol, setostearil alkol ya da bunlarin karisimlari arasindan seçilebilmektedir. Suitable rate controlling agents are ethyl acrylate, ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, zein, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylseI'L'ylose E4M, hydroxypropyl methylcellulose K100MCR, hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, alginic acid, pectin, polyglucuronic acid, polygalacturonic acid, chondroitic sulfate, carrageenan, Iambda carrageenan, iota carrageenan, fursellaran, xanthan gum, an acrylic acid polymer, carbopol, agar, guar gum, psyllium gum, gellan gum, locust bean gum, tara gum, tamarind gum, gum arabic, wolflan, galactomannan, glucomannan, nitrocellulose, methylcellulose, proteoglycan, glycoprotein, actin, tubulin, hemoglobin, insulin, fibrin, albumin, myosin, collagen, casein, pullulan, chitosan, glycerol, propylene glycol, macrogols, phthalate esters, dibutyl sebacetate, citrate esters, triacetin, castor oil, acetylated monoglycerides, shredded coconut oil, hydrogenated vegetable oil, hydrogenated castor oil, carnauba wax, candellia wax, beeswax, paraffin wax, stearic acid, glyceryl behenate, cetyl alcohol, cetostearyl alcohol or can be chosen among the mixtures of these.

Bu düzenlemeye göre farmas'otik kompozisyon %5-85 (ala) arasindaki bir miktarda hiz kontrol edici ajan içermektedir. According to this embodiment, the pharmaceutical composition is hydrated in an amount of 5 to 85% (ala). Contains controlling agent.

Uygun lubrikanlar magnezyum stearat, kolloidal silikon dioksit, kalsiyum stearat, çinko stearat, talk, mumlar, borik asit, hidrojenlenmis bitkisel yag, sodyum klorat, magnezyum laurik sülfat, sodyum oleat, sodyum asetat, sodyum benzoat, polietilen glikol, stearik asit, yag asidi, fumarik asit, gliseril palmito sülfat, sodyum stearil fumarat, sodyum laurik sülfat ya da bunlarin karisimlari arasindan seçilebilmektedir. Suitable lubricants are magnesium stearate, colloidal silicon dioxide, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauric sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, oil acid, fumaric acid, glyceryl palmito sulfate, sodium stearyl fumarate, sodium lauric sulfate or can be chosen among the mixtures of these.

Uygun glidanlar talk, alüminyum silikat, koloidal silika, nisasta ya da bunlarin karisimlari arasindan seçilebilmektedir. Suitable glidants are talc, aluminum silicate, colloidal silica, starch or mixtures thereof. can be selected among

Uygun dagiticilar çapraz-bagli polivinil pirolidon (krospovidon), povidon, çapraz bagli karboksimetil selüloz (kroskarmeloz sodyum), düsük-ikameli hidroksipropil selüloz, prejelatinize nisasta, sodyum karboksimetil selüloz, kalsiyum karboksimetil selüloz, karboksimetil selüloz, dokusat sodyum, guar sakizi, düsük ikameli hidroksipropil selüloz, poliakrilin potasyum, sodyum aljinat, misir nisastasi, sodyum nisasta glikolat, aljinik asit, aljinatlar, iyon-degisim reçinesi, magnezyum aluminyum silis, sodyum dodesil sülfat, poloksamer, sodyum glisin karbonat, sodyum laurik sülfat ya da bunlarin karisimlari arasindan seçilebilmektedir. Suitable dispersants 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, low substituted hydroxypropyl cellulose, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resin, magnesium aluminum silica, sodium dodecyl sulfate, poloxamer, sodium glycine carbonate, sodium lauric sulfate or mixtures thereof can be selected among

Uygun plastiklestiriciler farkli moleküler agirliklarda polietilen glikoller, propilen glikol ya da bunlarin karisimlari arasindan seçilebilmektedir. Suitable plasticizers are polyethylene glycols of different molecular weights, propylene glycol or can be chosen among the mixtures of these.

Uygun koruyucular metil paraben, propil paraben ve bunlarin tuzlari (sodyum, potasyum gibi), sodyum benzoat, sitrik asit, benzoik asit, bütillenmis hidroksitoluen ya da bütillenmis hidroksianizol, m-kresol, fenol ya da bunlarin karisimlari arasindan seçilebilmektedir. Suitable preservatives are methyl paraben, propyl paraben and their salts (sodium, potassium). such as sodium benzoate, citric acid, benzoic acid, butylated hydroxytoluene or butylated hydroxyanisole, m-cresol, phenol, or mixtures thereof.

Uygun tatlandiricilar aspartam, potasyum asesülfam, sodyum sakkarinat, neohesperidin dihidrokalkon, sukraloz, sakarin, sukroz, glikoz, Iaktoz, fruktoz gibi sekerler ya da mannitol, sorbitol, ksilitol, eritritol gibi seker alkolleri ya da bunlarin karisimlari arasindan seçilebilmektedir. Suitable sweeteners are aspartame, potassium acesulfame, sodium saccharinate, neohesperidin sugars such as dihydrochalcone, sucralose, saccharin, sucrose, glucose, lactose, fructose or mannitol, sugar alcohols such as sorbitol, xylitol, erythritol or their mixtures. can be selected.

Uygun tat vericiler mentol, nane, tarçin, çikolata, vanilin ya da kiraz, portakal, çilek, üzüm, Frenk üzümü, ahududu, muz, kirmizi meyveler, yabani meyveler gibi meyve özlerini ya da bunlarin karisimlari arasindan seçilebilmektedir. Suitable flavorings are menthol, mint, cinnamon, chocolate, vanilla or cherry, orange, strawberry, grape, Fruit extracts such as blackcurrant, raspberry, banana, red berries, wild berries, or can be chosen among the mixtures of these.

Uygun boyar maddeler ferrik oksit, titanyum dioksit, Gida, Ilaç ve Kozmetik (FD&C) boyalari (FD&C mavisi, FD&C yesili, FD&C kirmizisi, FD&C sarisi, FD&C koyu kirmizi boyasi gibi), ponkau, çivit Ilaç ve Kozmetik (D&C) mavisi, indigotin FD&C mavisi, karmoisin indigotin (indigo Karmin): demir oksitler (demir oksit kirmizi, sari, siyah gibi), kuinolin sarisi, alev kirmizisi, karmin, karmoisin, gün batimi sarisi ya da bunlarin karisimlari arasindan seçilebilmektedir. manitol, eritritol gibi seker alkolleri, düsük ikameli hidroksipropil selüloz, hidroksipropil selüloz, hidroksipropil metilselüloz, polivinilpirolidon, polivinil alkol, metilselüloz, hidroksietil metilselüloz ya da bunlarin karisimlari arasindan seçilmektedir. Suitable dyestuffs ferric oxide, titanium dioxide, Food, Pharmaceutical and Cosmetic (FD&C) dyes (such as FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C dark red dye), ponkau, indigo Pharmaceuticals and Cosmetics (D&C) blue, indigotin FD&C blue, carmoicin indigotine (indigo Carmine): iron oxides (such as iron oxide red, yellow, black), quinoline yellow, flame red, carmine, karmoisin, sunset yellow, or a mixture of these. can be selected. sugar alcohols such as mannitol, erythritol, low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, hydroxyethyl methylcellulose or mixtures thereof.

Vorapaksar ve metoprolol arasindaki farmasbtik uyumsuzluk problemine göre mevcut bulus vorapaksar ve metoprolol tabakalarini birbirinden ayiracak ya da vorapaksar peletlerini ve metoprolol peletlerini kaplayacak sekilde ortada yer alan inert ajanlar içeren bir farmas'otik kompozisyon saglamaktadir. Inert ajanlar sayesinde vorapaksar ve metoprolol molekülleri arasindaki etkilesim önlenir ve ayni zamanda da bu moleküllerin dozaj formu içerisinde stabil kalmasi saglanir. Buna ilaveten bir diger 'Önemli problem de farkli salim özelliklerine sahip etken maddelerin kompozisyonlarinin inert ajanlarla ayni formda saglanabiliyor olmasidir.The present invention according to the pharmaceutical incompatibility problem between Vorapaksar and metoprolol to separate the vorapaksar and metoprolol layers, or to separate the vorapaksar pellets and A pharmaceutical containing inert agents placed in the middle to coat metoprolol pellets. provides composition. Vorapaksar and metoprolol molecules thanks to inert agents The interaction between them is prevented and at the same time these molecules are stable in the dosage form. is ensured to remain. In addition, another 'Important problem is that they have different release properties. The fact that the compositions of active substances can be supplied in the same form as inert agents.

Bu nedenle vorapaksar ve metoprolol molekülleri birbirleriyle etkilesmeyecek ve ayni zamanda da kendi formlarinda stabil kalacak sekilde formüle edilmislerdir. Therefore, vorapaksar and metoprolol molecules will not interact with each other and They are also formulated to remain stable in their own form.

Bu nedenle mevcut bulus vorapaksar ve metoprolol moleküllerini ayri ayri içermektedir ve özelligi ise bu molekülleri birlikte ve hizli bir biçimde salmasidir. Therefore, the present invention includes vorapaksar and metoprolol molecules separately and Its feature is that it releases these molecules together and rapidly.

Bulusun bir düzenlemesinde farmasötik kompozisyon istege bagli olarak bir kaplama içerebilir ki bu kaplama polivinilalkol bazli filmler, polietilen glikol, etil akrilat ve metil metakrilat kopolimer dispersiyon, sari demir oksit, polivinil alkol, polivinil alkol-polietilen glikol kopolimerler, hidroksipropil metil selüloz, etil selüloz, etilselüloz dispersiyonlari, polivinilpirolidon, polivinilvinilpirolidon-viniI asetat kopolimer (PVP-VA), pigmentler, boyalar, titanyum dioksit, demir oksit, talk, demir oksit, triasetin, polimetilmetakrilat kopolimerler ya da bunlarin karisimlari arasindan seçilmektedir.In one embodiment of the invention, the pharmaceutical composition optionally includes a coating. This coating may contain polyvinylalcohol based films, polyethylene glycol, ethyl acrylate and methyl methacrylate copolymer dispersion, yellow iron oxide, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymers, hydroxypropyl methyl cellulose, ethyl cellulose, ethylcellulose dispersions, polyvinylpyrrolidone, polyvinylvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), pigments, dyes, titanium dioxide, iron oxide, talc, iron oxide, triacetin, polymethylmethacrylate copolymers or selected from among their mixtures.

Bulusun farmasötik kompozisyonlari dogrudan baski, kuru granülasyon, yas granülasyon gibi teknik alanda uzman kisilerin iyi bildigi geleneksel teknolojilerle hazirlanabilir. Direkt basim sirasinda aktif madde ve eksipiyanlar karistirilir, elenir ve dozaj formlari seklinde basilir. Yas granülasyon esnasinda içerik maddeleri karistirilir ve bir granülasyon sivisi ile granüle edilir.Pharmaceutical compositions of the invention include direct pressure, dry granulation, wet granulation. It can be prepared using traditional technologies well known to those skilled in the technical field. direct printing During the process, the active substance and excipients are mixed, sieved and pressed into dosage forms. Mourning During granulation, the ingredients are mixed and granulated with a granulation liquid.

Granülasyon prosesi istenen homojenlikte topaklar saglamaktadir. Karisim kurutulur ve elekteri geçirilir ve istege bagli olarak ilave eksipiyanlarla karistirilir. Son olarak dozaj formlari elde etmek üzere basilir. Buna ilaveten bu yeni farmasötik kompozisyon sivi yatakli granülasyon teknigi ya da ekstrüzyon/sferonizasyon (küre haline getirme) ya da püskürterek kurutma ve Iiyofilizasyon gibi çesitli tekniklerle üretilmektedir. The granulation process provides lumps of desired homogeneity. The mixture is dried and the electricity is passed and optionally mixed with additional excipients. Finally, dosage forms printed to obtain. In addition, this new pharmaceutical composition is liquid bedded. granulation technique or extrusion/spheronization or spraying It is produced by various techniques such as drying and lyophilization.

Farmasötik kompozisyon kardiyovasküler hastaliklarin ya da bozukluklarin tedavisinde kullanim içindir. Pharmaceutical composition for the treatment of cardiovascular diseases or disorders it is for my use.

Mevcut bulusun bir görüsü de, FAR-1 reseptörlerinin antagonize edilmesiyle iliskili bir ya da birden fazla durumun tedavisi, iyilestirilmesi ya da önlenmesine yönelik bir ilacin üretilmesi için vorapaksar ve metoprololün kullanilmasidir. One aspect of the present invention is that one or more associated with the antagonism of FAR-1 receptors manufacture of a drug for the treatment, amelioration, or prevention of more than one condition The use of vorapaksar and metoprolol for

Bu, tedaviye ihtiyaç duyan bir memeliye vorapaksar ve metoprololün terapötik olarak etkili bir miktarini uygulayarak PAR-l reseptörünün antagonize edilmesiyle iliskili durumlarin etkili yönetimi için günde bir kez dozlamanin kullanimina olanak saglamaktadir. PAR-1 reseptörünü antagonize ederek tedavi edilebilecek ya da önlenebilecek durumlar akut koroner sendromlari (ACS), sekonder önlemeyi, periferal atardamar hastaligini (PAD), trombozu, aterosklerozu, restenozu, hipertansiyonu, anjin pektorisi, ritim bozuklugunu, kalp yetmezligini, miyokardiyal enfarktüsü (MI), glomerülonefriti, trombotik inmeyi, tromboembolitik inmeyi, derin damar trombozunui hormon replasman terapisiyle iliskili bir kardiyovasküler hastalik olan venöz embolisini, renal iskemiyi, serebral inmeyi, serebral iskemiyi, serebral enfarktüsü, migreni, ya da renal vasküler homeostazisi içermektedir. FAR-1 reseptörünü antagonize ederek tedavi edilebilecek diger durumlar Ml geçmisine sahip hastalarda aterotrombotik durumlarin azaltilmasi ve kardiyovasküler ölüm, MI, inme ve ani koroner revaskülarizasyon gibi uç nokta olaylarin görülme sikliginin azalmasidir.This is a therapeutically effective solution of vorapaxar and metoprolol to a mammal in need of treatment. Effectiveness of the conditions associated with antagonizing the PAR-1 receptor by applying the amount of It allows the use of once-daily dosing for management. PAR-1 Conditions that can be treated or prevented by antagonizing its receptor are acute coronary syndromes (ACS), secondary prevention, peripheral artery disease (PAD), thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, cardiac failure, myocardial infarction (MI), glomerulonephritis, thrombotic stroke, thromboembolism stroke, deep vein thrombosis, a cardiovascular disease associated with hormone replacement therapy. venous embolism, renal ischemia, cerebral stroke, cerebral ischemia, cerebral infarction, migraine, or renal vascular homeostasis. FAR-1 receptor Other conditions that can be treated by antagonizing in patients with a history of MI reduction of atherothrombotic states and cardiovascular death, MI, stroke and sudden coronary Reducing the incidence of end-point events such as revascularization.

Ornekler: Ornek-1: Vorapaksar HS faz + metoprolol KS faz Hemen salimli faz (Vorapaksar) miktar %'si (ala) Vorapaksar %5,00-95,00 Misir nisastasi Polivinilpirolidon (PVP) %O,50-5,00 Mikrokristalin selüloz (MCC) %20,00-90,00 Kolloidal silikon dioksit %O,10-2,00 Magnezyum stearat %O,25-5,00 Kontroll'ü salimli faz (Metoprolol) miktar %'si (ala) Metoprolol %5,00-95,00 Hidroksipropil metilselüloz E4M (HPMC E4M) %2,00-25,00 Hidroksipropil metilsel'üloz K1OOMCR (HPMC %2,00-25,00 K1OOMCR) Mikrokristalin selüloz (MCC) %20,00-90,00 Kolloidal silikon dioksit %O,10-2,00 Magnezyum stearat %0,25-5,00 Farmasötik formülasyonun hemen salimli fazinin hazirlanma prosesi asagidaki adimlari içermektedir: Vorapaksar, Iaktoz monohidrat, misir nisastasi, MCC'nin karistirilmasi; a) adimindaki karisimin PVP ile gran'L'iIe edilmesi; b) adimindaki karisimin elenmesi; C) adimindaki gran'üllerin kolloidal silikon dioksit ve magnezyum stearat ile karistirilmasi. Examples: Example-1: Vorapaksar HS phase + metoprolol KS phase Immediate-release phase (Vorapaksar) amount % (ala) Vorapaksar 5.00-95.00% Corn starch Polyvinylpyrrolidone (PVP) 0,50-5.00% Microcrystalline cellulose (MCC) 20.00%-90.00 Colloidal silicon dioxide 0,10-2.00% Magnesium stearate 0.25-5.00% Controlled-release phase (Metoprolol) % of amount (take) Metoprolol 5.00-95.00 Hydroxypropyl methylcellulose E4M (HPMC E4M) 2.00-25.00% Hydroxypropyl methylcellulose K1OOMCR (HPMC 2.00-25.00% K1OOMCR) Microcrystalline cellulose (MCC) 20.00%-90.00 Colloidal silicon dioxide 0,10-2.00% Magnesium stearate 0.25-5.00% The following steps are involved in the preparation process of the immediate release phase of the pharmaceutical formulation. includes: Mixing Vorapaksar, Ilactose monohydrate, corn starch, MCC; granulating the mixture of step a) with PVP; b) elimination of the mixture in step; C) with colloidal silicon dioxide and magnesium stearate of the granules in step mixing.

Kontrollü salimli faz (Metoprolol) Farmasötik formülasyonun kontrollü salimli fazinin hazirlanma prosesi asagidaki adimlari Metoprolol, HPMC E4M ve mikrokristalin selülozun karistirilmasi; a) adimindaki karisimin suyla veya susuz granüle edilmesi (yas veya kuru içermektedir: granülasyon); c) b) adimindaki karisimin elenmesi; d) 0) adimindaki granüllerin HPMC K100lVICR, kolloidal silikon dioksit ve magnezyum stearat ile karistirilmasi.Controlled release phase (Metoprolol) The following steps are involved in the preparation process of the controlled release phase of the pharmaceutical formulation. Mixing metoprolol, HPMC E4M and microcrystalline cellulose; Granulating the mixture of step a) with or without water (wet or dry) includes: granulation); c) eliminating the mixture of step b); d) The granules of step 0) HPMC K100lVICR, colloidal silicon dioxide and mixing with magnesium stearate.

Elde edilen bu farkli karisimlar; i. Çok tabakali tabletler ya da mini tabletler ya da pelletler halinde basilir. istege bagli olarak bu çok tabakali tablet veya pelletlerin kaplanmasi ii. ya da kapsüllere doldurulmasi da mümkündür. These different mixtures obtained; I. Compressed as multilayer tablets or mini-tablets or pellets. request coating of these multilayer tablets or pellets, depending on ii. Or it can be filled into capsules.

Ornek-2: Metaprolol KS Faz üzerine Kaplanmis Vorapaksar HS faz Hemen salimli faz (Vorapaksar) miktar %'si (ala) Vorapaksar %5,00-95,00 Hidroksipropil metil selüloz (HPMC) %5,00-50,00 Polietilen glikol %5,00-30,00 Kontrollü salimli faz (Metoprolol) miktar %'si (ala) Metoprolol %5,00-95,00 Polietilen oksit %5,00-85,00 Laktoz monohidrat %5,00-75,00 Kolloidal silikon dioksit %O,10-2,00 Magnezyum stearat %O,25-5,00 Hemen salimli fa_z (Vorapaksarl Farmasötik formülasyonun hemen salimli fazinin hazirlanma prosesi asagidaki adimlari içermektedir: a) Vorapaksar, HPMC ve polietilenin karistirilmasi; b) a) adimindaki karisima su eklenmesi; 0) b) adimindaki karisimin homojenize edilmesi; Kontrollü salimli faz (Metoprolol) Farmasötik formülasyonun kontrollü salimli fazinin hazirlanma prosesi asagidaki adimlari içermektedir: a) metoprolol, Iaktoz monohidrat, polietilen oksidin karistirilmasi; a) adimindaki karisimin suyla veya susuz granüle edilmesi (yas veya kuru granülasyon); b) adimindaki karisimin elenmesi; C) adimindaki gran'ullerin kolloidal silikon dioksit ve magnezyum stearat ile karistirilmasi. Example-2: Vorapaksar HS phase Coated on Metaprolol KS Phase Immediate-release phase (Vorapaksar) amount % (ala) Vorapaksar 5.00-95.00% Hydroxypropyl methyl cellulose (HPMC) 5.00-50.00 Polyethylene glycol 5.00-30.00% Controlled-release phase (Metoprolol) amount % (ala) Metoprolol 5.00-95.00 Polyethylene oxide 5.00-85.00 Lactose monohydrate 5.00-75.00 Colloidal silicon dioxide 0,10-2.00% Magnesium stearate 0.25-5.00% Immediate release fa_z (Vorapaksarl The following steps are involved in the preparation process of the immediate release phase of the pharmaceutical formulation. includes: a) mixing Vorapaksar, HPMC and polyethylene; b) adding water to the mixture of step a); 0) homogenizing the mixture of step b); Controlled release phase (Metoprolol) The following steps are involved in the preparation process of the controlled release phase of the pharmaceutical formulation. includes: a) mixing of metoprolol, lactose monohydrate, polyethylene oxide; Granulating the mixture of step a) with or without water (wet or dry) granulation); b) elimination of the mixture in step; C) granules in step C with colloidal silicon dioxide and magnesium stearate. mixing.

KS fazin tabletler halinde basilmasi. Compression of the KS phase in tablets.

Son olarak, elde edilen bu KS tabletlerinin HS faz Vorapaksar ile kaplanir. Finally, the HS phase of these KS tablets obtained is coated with Vorapaksar.

Ornek 3: Vorapaksar HS faz + Metoprolol KS faz (tablet içinde tablet teknolojisi) miktar %'si (ala) Vorapaksar Mikrokristalin selüloz (MCC) Misir nisastasi Krospovidon %2,00-5,00 Polivinilpirolidon (PVP) %O,50-5,00 Magnezyum stearat %O,25-5,00 Kontroll'ü salimli faz (Metoprolol) miktar %'si (ala) Metoprolol Polietilen oksit Laktoz monohidrat Kolloidal silikon dioksit Magnezyum stearat Farmasötik formülasyonun hemen salimli fazinin hazirlanma prosesi asagidaki adimlari içermektedir: a) Vorapaksar, MCC, misir nisastasi, krospovidonun karistirilmasi; b) a) adimindaki karisimin polivinilpirolidon (PVP) ile gran'ule edilmesi; b) adimindaki karisimin elenmesi; d) 0) adimindaki granüllerin talk ve magnezyum stearat ile karistirilmasi.Example 3: Vorapaksar HS phase + Metoprolol KS phase (tablet-in-tablet technology) % of amount (take) Vorapaksar Microcrystalline cellulose (MCC) Corn starch Crospovidone 2.00-5.00% Polyvinylpyrrolidone (PVP) 0,50-5.00% Magnesium stearate 0.25-5.00% Controlled-release phase (Metoprolol) % of amount (take) metoprolol polyethylene oxide lactose monohydrate colloidal silicon dioxide magnesium stearate The following steps are involved in the preparation process of the immediate release phase of the pharmaceutical formulation. includes: a) mixing Vorapaksar, MCC, corn starch, crospovidone; b) granulating the mixture of step a) with polyvinylpyrrolidone (PVP); b) elimination of the mixture in step; d) mixing the granules of step 0) with talc and magnesium stearate.

Kontrollü salimli faz Meto rolol Farmasötik formülasyonun kontrollü salimli fazinin hazirlanma prosesi asagidaki adimlari içermektedir: a) metoprolol, Iaktoz monohidrat ve polietilen oksidin karistirilmasi; b) a) adimindaki karisimin suyla veya susuz granüle edilmesi (yas veya kuru granülasyon); 0) b) adimindaki karisimin elenmesi; d) 0) adimindaki granüllerin kolloidal silikon dioksit ve magnezyum stearat ile karistirilmasi.Controlled-release phase Metorolol The following steps are involved in the preparation process of the controlled release phase of the pharmaceutical formulation. includes: a) mixing metoprolol, lactose monohydrate and polyethylene oxide; b) Granulating the mixture of step a) with or without water (wet or dry) granulation); 0) eliminating the mixture of step b); d) the granules of step 0) with colloidal silicon dioxide and magnesium stearate. mixing.

Elde edilen bu farkli karisimlarda; i. Tablet içinde tablet teknolojisi kullanilir. Istege bagli olarak bu tablet kaplanabilir. In these different mixtures obtained; I. Tablet technology is used within the tablet. Optionally this tablet can be coated.

Ornek-4: Vorapaksar HS faz + Metoprolol KS faz Kontrollü salimli faz (Vorapaksar) miktar %'si (ala) Vorapaksar %5,00-95,00 Polietilen oksit %0,50-25,00 Sodyum Aljinat %2,00-20,00 Krospovidon %1 ,DO-5,00 Aluminum silikat %0,10-1,00 Kalsiyum stearat %0,10-2,00 Kontrollü salimli faz (Metoprolol) miktar %'si (ala) Metoprolol %5,00-95,00 Hidroksipropil selüloz %5.00-40,00 Etil selüloz %1 ,DO-20,00 Aljinik asit %1 ,DO-5,00 Stearik asit %0,50-5,00 Kolloidal silikon dioksit %O.10-2,00 Kontrollü salimli faz (Vorapaksar) Farmasötik formülasyonun kontrollü salimli fazinin hazirlanma prosesi asagidaki adimlari içermektedir: a) vorapaksar, polietilen oksit ve sodyum aljinatin karistirilmasi; b) a) adimindaki polietilen glikol ile granüle edilmesi; c) b) adimindaki karisimin elenmesi; d) C) adimindaki granüllerin krospovidon, aluminyum silikat ve kalsiyum stearat ile karistirilmasi.Example-4: Vorapaksar HS phase + Metoprolol KS phase Controlled-release phase (Vorapaksar) amount % (ala) Vorapaksar 5.00-95.00% Polyethylene oxide 0.50-25.00% Sodium Alginate 2.00-20.00% Crospovidone 1% ,DO-5.00 Aluminum silicate 0.10-1.00% Calcium stearate 0.10-2.00% Controlled-release phase (Metoprolol) amount % (ala) Metoprolol 5.00-95.00 Hydroxypropyl cellulose 5.00-40.00% Ethyl cellulose 1% ,DO-20.00 Alginic acid 1% ,DO-5.00 Stearic acid 0.50-5.00% Colloidal silicon dioxide 0.10-2.00% Controlled release phase (Vorapaksar) The following steps are involved in the preparation process of the controlled release phase of the pharmaceutical formulation. includes: a) mixing vorapaxar, polyethylene oxide and sodium alginate; b) granulating with the polyethylene glycol of step a); c) eliminating the mixture of step b); d) The granules of step C) are mixed with crospovidone, aluminum silicate and calcium stearate. mixing.

Kontrollü salimli faz (Metoprolol) Farmasötik formülasyonun kontrollü salimli fazinin hazirlanma prosesi asagidaki adimlari içermektedir: a) Metoprolol, hidroksipropil selüloz, etil selülozün karistirilmasi; b) a) adimindaki karisimin aljinik asit ile granüle edilmesi; (3) b) adimindaki karisimin elenmesi; d) c) adimindaki granüllerin stearik asit ve kolloidal silikon dioksitle karistirilmasi.Controlled release phase (Metoprolol) The following steps are involved in the preparation process of the controlled release phase of the pharmaceutical formulation. includes: a) mixing of metoprolol, hydroxypropyl cellulose, ethyl cellulose; b) granulating the mixture of step a) with alginic acid; (3) eliminating the mixture of step b); d) mixing the granules of step c) with stearic acid and colloidal silicon dioxide.

Elde edilen bu farkli karisimlar; i. Çok tabakali tabletler halinde basilir. lstege bagli olarak bu çok katmanli tabletin kaplanmasi ii. ya da kapsüllere doldurulmasi da mümkündür.These different mixtures obtained; I. Compressed as multilayer tablets. Optionally, this multi-layer tablet coating ii. Or it can be filled into capsules.

Claims (1)

ISTEM LER Vorapaksar ya da bunun farmasötik olarak kabul edilebilir bir tuzunu ve metoprolol ya da bunun farmasötik olarak kabul edilebilir bir tuzunu ve en az bir farmasötik olarak kabul edilebilir eksipiyani içeren bir farmasötik kompozisyon olup özelligi, etken maddelerden en az birinin kontrollü salim formunda olmasidir. lstem 1'e göre farmasötik kompozisyon olup özelligi, vorapaksar miktarinin 0,01 mg mg arasinda olmasidir. lstem 2'ye göre farmasötik kompozisyon olup özelligi, vorapaksarin farmasötik olarak kabul edilebilir tuzunun tercihen vorapaksar sülfat olmasidir. lstem 1'e göre farmasötik kompozisyon olup özelligi, metoprolol miktarinin 5 mg ve mg arasinda olmasidir. lstem 4'e göre farmasötik kompozisyon olup özelligi, metoprololün farmasötik olarak kabul edilebilir tuzunun tercihen metoprolol tartarat, metoprolol süksinat ve metoprolol fumarat olmasidir. lstem 1'e göre farmasötik kompozisyon olup özelligi, farmasötik kompozisyonun 0,5 mg ve 20 mg arasinda bir miktarda vorapaksar ve 15 mg ve 220 mg arasinda bir miktarda metoprolol içermesidir. lstem G'ya göre farmasötik kompozisyon olup özelligi, metoprolol'un vorapaksara oraninin 1 ila 220 (ala) araliginda, tercihen 1 ila 100 (ala) araliginda ve en tercihen 2 ila 80 (ala) araliginda olmasidir. lstem 1'e göre farmasötik kompozisyon olup özelligi, söz konusu farmasötik kompozisyonun vorapaksarin hemen salimli fazini ve metoprololün kontrollü salimli fazini ve bir hiz kontrol edici ajan olan en az bir farmasötik olarak kabul edilebilir eksipiyani içermesidir. Onceki istemlerden herhangi birine göre farmasötik kompozisyon olup özelligi, farmasötik kompozsiyonun oral, parenteral, intranazal, dilalti, transdermal, transmukozal, oftalmik, intravenöz, pulmoner, intramasküler ya da rektal yolla uygulanmasi; tercihen de oral yolla uygulanmasidir. Onceki istemlerden herhangi birine göre farmasötik kompozisyon olup özelligi, söz konusu farmasötik kompozisyonun sikistirilmis tabletler, kaplanmis ya da kaplanmamis tabletler, çok tabakali tabletler, mini tabletler, bukkal tabletler, diIaIti tabletler, modifiye salim tabletleri, film kapli tabletler, midede dagilan tabletler, pelletler, efervesan kompozisyonlar, haplar, kapsüller, sert jelatin kapsüller, tozlar, kapli boncuk sistemleri, granüller, mikroküreler, iyon degisim reçinesi sistemleri, steril çözeltiler ya da süspansiyonlar, ampL'iIler, parenteral sistemler, kremler, jeller, drajeler, oral yolla uygulanabilir filmler, çözeltiler, katilar, süspansiyonlar, koloidal dispersiyonlar, em'ülsiyonlar seklinde formüle edilmesidir. Onceki istemlerden herhangi birine göre farmasötik kompozisyon olup özelligi, söz konusu farmasötik kompozisyonun günde bir ya da iki kez uygulanmasi; tercihen günde bir kez uygulanmasidir. Onceki istemlerden herhangi birine göre farmasötik kompozisyon olup özelligi, söz konusu farmasötik kompozisyonun insan ya da hayvanlar dahil olmak 'üzere tedaviye ihtiyaci olan herhangi bir hastaya uygulanmasidir. yardimci maddenin tamponlama ajanlari, stabiliz'orler, antioksidanlar, baglayicilar, seyrelticiler, dagitici ajanlar, hiz kontrol edici ajanlar, Iubrikanlar, glidanlar, dagiticilar, plastiklestiriciler, koruyucular, tatlandiricilar, tat vericiler, renklendiriciler, inert ajanlar, kaplama ajanlari ya da bunlarin karisimlari arasindan seçilmesidir. lstem 13'e göre farmasötik kompozisyon olup 'Özelligi, hiz kontrol edici ajanlarin etil akrilat, etil metakrilat kopolimer, etilsel'üloz, metilsel'üloz, hipromelloz fitalat, polidekstroz, polivinilasetat fitalat, zein, polivinilpirolidon, polivinil alkol, polivinil asetat, hidroksipropil selüloz, hidroksipropil metilselüloz, hidroksipropil metilsel'uloz E4M, hidroksipropil metilselüloz K100MCR, hidroksietil selüloz, hidroksimetil selüloz, jelatin, polietilen oksit, akasya, dekstrin, nisasta, polihidroksietilmetakrilat, sodyum karboksimetilseli'iloz, karboksimetil selüloz, sodyum aljinat, aljinik asit, pektin, poliglukoronik asit, poligalakturonik asit, kondroitik s'L'iIfate, karajenan, Iambda karajenan, iota karajenan, fursellaran, ksantan sakizi, bir akrilik asit polimeri, karbopol, agar, guar sakizi, pisilyum sakizi, gellan sakizi, keçi boynuzu sakizi, tara sakizi, tamarind sakizi, arap sakizi, kurdlan, galaktomannan, glukomannan, nitroselüloz, metilsel'üloz, proteoglikan, glikoprotein, aktin, tubulin, hemoglobin, insülin, fibrin, albumin, miyosin, kolajen, kazein, pullulan, kitozan, gliserol, propilen glikol, makrogoller, fitalat esterleri, dibutil sebasetat, sitrat esterleri, triasetin, hint yagi, asetillenmis monogliseridler, parçalara ayrilmis hindistan cevizi yagi, hidrojenlenmis bitkisel yag, hidrojenlenmis hint yagi, karnauba mumu, kandellia mumu, balmumu, parafin mumu, stearik asit, gliseril behenat, setil alkol, setostearil alkol ya da bunlarin karisimlari arasindan seçilebilmesidir. 85 (a/a) arasinda bir oranda mevcut olmasidir. Onceki istemlerden herhangi birine göre farmasbtik kompozisyon olup özelligi, farmas'otik kompozisyonun kardiyovasküler hastaliklarin ya da bozukluklarin tedavisinde kullanim için olmasidir.Claims A pharmaceutical composition comprising Vorapaksar or a pharmaceutically acceptable salt thereof and metoprolol or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, characterized in that at least one of the active ingredients is in a controlled release form. It is a pharmaceutical composition according to claim 1, characterized in that the amount of vorapaxar is between 0.01 mg and mg. The pharmaceutical composition according to claim 2, characterized in that the pharmaceutically acceptable salt of vorapaxarin is preferably vorapaxar sulfate. It is a pharmaceutical composition according to claim 1, characterized in that the amount of metoprolol is between 5 mg and mg. The pharmaceutical composition according to claim 4, characterized in that the pharmaceutically acceptable salt of metoprolol is preferably metoprolol tartrate, metoprolol succinate and metoprolol fumarate. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition contains vorapaxar in an amount between 0.5 mg and 20 mg and metoprolol in an amount between 15 mg and 220 mg. Pharmaceutical composition according to claim G, characterized in that the ratio of metoprolol to vorapaxara is in the range of 1 to 220 (ala), preferably in the range of 1 to 100 (ala), and most preferably in the range of 2 to 80 (ala). The pharmaceutical composition according to claim 1, characterized in that said pharmaceutical composition contains the immediate-release phase of vorapaxarin and the controlled-release phase of metoprolol and at least one pharmaceutically acceptable excipient which is a rate-controlling agent. The pharmaceutical composition according to any of the preceding claims, characterized in that the pharmaceutical composition is administered by oral, parenteral, intranasal, sublingual, transdermal, transmucosal, ophthalmic, intravenous, pulmonary, intramuscular or rectal route; preferably orally. Pharmaceutical composition according to any one of the preceding claims, characterized in that said pharmaceutical composition is composed of compressed tablets, coated or uncoated tablets, multilayered tablets, mini-tablets, buccal tablets, dental tablets, modified release tablets, film-coated tablets, gastric disintegrating tablets, pellets, effervescent compositions, pills, capsules, hard gelatin capsules, powders, coated bead systems, granules, microspheres, ion exchange resin systems, sterile solutions or suspensions, amplifications, parenteral systems, creams, gels, dragees, orally applicable films, It is formulated as solutions, solids, suspensions, colloidal dispersions, emulsions. The pharmaceutical composition according to any one of the preceding claims, characterized in that said pharmaceutical composition is administered once or twice a day; preferably once a day. The pharmaceutical composition according to any one of the preceding claims, characterized in that said pharmaceutical composition is administered to any patient in need of treatment, including humans or animals. buffering agents, stabilizers, antioxidants, binders, diluents, dispersing agents, rate controlling agents, lubricants, glidants, dispersants, plasticizers, preservatives, sweeteners, flavorings, colorants, inert agents, coating agents, or mixtures thereof. is to be chosen. Pharmaceutical composition according to claim 13, characterized in that the rate controlling agents are ethyl acrylate, ethyl methacrylate copolymer, ethylcellulose, methylcellulose, hypromellose phthalate, polydextrose, polyvinylacetate phthalate, zein, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl cellulose , hydroxypropyl methylcellulose, hydroxypropyl methylcellulose E4M, hydroxypropyl methylcellulose K100MCR, hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, acacia, dextrin, starch, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, sodium carboxymethylcellulose, alcholic acid, polygalacturonic acid, chondroitic s'L'ilIfate, carrageenan, Iambda carrageenan, iota carrageenan, fursellaran, xanthan gum, an acrylic acid polymer, carbopol, agar, guar gum, psyllium gum, gellan gum, locust bean gum, tara gum tamarind gum, gum arabic, wolflan, galactomannan, glucomannan, nitrocellulose, methylcellulose, proteoglycan, glycoprote In, actin, tubulin, hemoglobin, insulin, fibrin, albumin, myosin, collagen, casein, pullulan, chitosan, glycerol, propylene glycol, macrogols, phthalate esters, dibutyl sebacetate, citrate esters, triacetin, castor oil, acetylated monoglycerides, fragmented Coconut oil, hydrogenated vegetable oil, hydrogenated castor oil, carnauba wax, candellia wax, beeswax, paraffin wax, stearic acid, glyceryl behenate, cetyl alcohol, cetostearyl alcohol or mixtures thereof. It is present at a rate of 85 (w/a). The pharmaceutical composition according to any one of the preceding claims, characterized in that the pharmaceutical composition is for use in the treatment of cardiovascular diseases or disorders.
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