TR2023011419A2

TR2023011419A2 - PHARMACEUTICAL COMPOSITION CONTAINING HIGH PARTICLE SIZE EMPAGLIFLOZIN AND A SECOND ACTIVE INGREDIENT

Info

Publication number: TR2023011419A2
Application number: TR2023/011419
Authority: TR
Inventors: Berat Beran Mehmet; Ozyurtlu Bari; Avci Recep; Nur Kobya Gozde; Ersoy Fuat; Yilmaz Esme; Yavuz Merve; Gun Ahmet
Original assignee: Berko İlaç Ve Ki̇mya Sanayi̇ Anoni̇m Şi̇rketi̇
Filing date: 2023-09-14
Publication date: 2023-12-21

Abstract

Mevcut buluş, Empagliflozin ve ikinci bir etken madde olarak Metformin Hidroklorür veya Linagliptin, çözünürlük arttırıcı bazik ajan içeren oral farmasötik bir kompozisyonlara ve bunların hazırlanmasına yönelik proses ile ilgilidir.The present invention relates to an oral pharmaceutical composition containing Empagliflozin and Metformin Hydrochloride or Linagliptin as a second active ingredient, a solubility enhancing basic agent, and a process for their preparation.

Description

TARIFNAME YÜKSEK PARTIKÜL BOYUTUNA SAHIP EMPAGLIFLOZIN VE IKINCI BIR ETKEN MADDE IÇEREN FARMASÖTIK KOMPOZISYON Teknik Alan Mevcut bulus, Empagliflozin ve ikinci bir etken madde, çözünürlük arttirici bazik ajan içeren oral farmasötik bir kompozisyonlara ve bunlarin hazirlanmasina yönelik proses ile Teknigin Durumu Empagliflozin oral yolla uygulanan seçici SGLT 2 inhibitörü yeni ve potent bir bilesiktir. DESCRIPTION EMPAGLIFLOZIN WITH HIGH PARTICLE SIZE AND A SECOND FACTOR PHARMACEUTICAL COMPOSITION CONTAINING SUBSTANCE Technical Field The present invention consists of Empagliflozin and a second active ingredient, a solubility enhancing basic agent an oral pharmaceutical composition containing and a process for preparing the same State of the Technology Empagliflozin is a new and potent orally administered selective SGLT 2 inhibitor.

Tip 2 diyabetli kisilerde glikoz kontrolünü iyilestirmek için kullanilan bir antidiyabetik ilaçtir. Empagliflozin, tip 2 diabetes mellituslu eriskinlerde glisemik kontrolün iyilestirilmesi ve tip 2 diabetes mellitus ve kanitlanmis kardiyovasküler hastaligi olan eriskin hastalarda kardiyovasküler ölüm riskini azaltmak için kullanilir. AB'de 23 Mayis 2014, ABD'de Agustos 2014 tarihinde diyet ve egzersizle yeterli kan sekeri kontrolü saglayamayan tip 2 diyabetli yetiskinlerin tedavisi için onaylanmistir. An antidiabetic used to improve glucose control in people with type 2 diabetes It is medicine. Empagliflozin improves glycemic control in adults with type 2 diabetes mellitus. treatment and treatment of type 2 diabetes mellitus and proven cardiovascular disease It is used to reduce the risk of cardiovascular death in adult patients. 23 May in the EU 2014, Adequate blood sugar control with diet and exercise in the USA in August 2014 It is approved for the treatment of adults with type 2 diabetes who do not have diabetes.

SGLT 2'nin inhibisyonu, glukozun renal reabsorpsiyonunu azaltir, böylece kan glukoz seviyelerinde sonuç olarak bir azalma ile idrarda glukoz atilimini destekler. tetrahydrofuran-3-oxyl ]benzyl}phenyl]-D-glucitol” olup, molekül agirligi 450.91'dir. Suda çok az çözünür, metanolde oldukça çözünür, etanol ve asetonitrilde az çözünür, %50 asetonitril/su karisiminda çözünür; toluende pratikçe çözünmez. Inhibition of SGLT 2 reduces renal reabsorption of glucose, thus increasing blood glucose It promotes the excretion of glucose in the urine with a consequent decrease in its levels. tetrahydrofuran-3-oxyl]benzyl}phenyl]-D-glucitol” and its molecular weight is 450.91. in water very slightly soluble, very soluble in methanol, slightly soluble in ethanol and acetonitrile, 50% soluble in acetonitrile/water mixture; Practically insoluble in toluene.

Formül 1 Empagliflozin biyoyararlanim sinifi 3'tür. Bu sinifa yüksek çözünürlük ve düsük permeabiliteye sahip bilesikler girer. Empagliflozin permeabilitesi hiz sinirlayici oldugundan Empagliflozin absorbsiyonu degiskendir. Formula 1 Empagliflozin bioavailability class is 3. This class includes high resolution and low Compounds with permeability enter. Empagliflozin permeability is rate limiting Therefore, the absorption of Empagliflozin is variable.

Metformin (Formül 2) kimyasal adi “N,N-dimethylimidodicarbonimidic diamide” olan bir biguanid antihiperglisemik ajandir. Karacigerdeki glikoz üretimini azaltarak, vücut dokularinin insülin duyarliligini artirarak GDF15 sekresyonunu artirarak çalisir. Metformin, özellikle tip 2 diyabet tedavisi için kullanilan birinci basamak bir ilaçtir. Metformin (Formula 2) is a biguanide whose chemical name is “N,N-dimethylimidodicarbonimidic diamide”. It is an antihyperglycemic agent. By reducing glucose production in the liver, body tissues increase insulin production. It works by increasing GDF15 secretion by increasing its sensitivity. Metformin, especially type 2 diabetes It is a first-line drug used for the treatment of

H30 NH NH Formül2 butyn-1-yl)-3,7dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]” olan, dipeptidil peptidaz-4 (DPP-4) enziminin inhibitörüdür. Genel olarak egzersiz ve diyetle birlikte tip 2 diyabeti tedavi o Frig-'f' Formül 3 etmek için kullanilir. H30 NH NH Formula2 butyn-1-yl)-3,7dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]”, dipeptidyl peptidase-4 It is an inhibitor of the (DPP-4) enzyme. Treating type 2 diabetes in general with exercise and diet o Phrygian-'f' Formula 3 It is used to.

Empagliflozin ve Metformin Hidroklorür içeren film kapli tabletler (5mg/850mg, 5mg/1000mg, tabletlerde eksipiyan olarak Misir nisastasi, Kopovidon , Koloidal susuz silika ve Magnezyum stearat içermektedir. Film-coated tablets containing Empagliflozin and Metformin Hydrochloride (5mg/850mg, 5mg/1000mg, Corn starch, Kopovidone, Colloidal anhydrous silica and Magnesium as excipients in tablets Contains stearate.

Empagliflozin ve Linagliptin içeren film kapli tabletler (10mg/5mg, 25mg/5mg) Glyxambi markasi ile piyasada bulunmaktadir. Glyxambi tabletlerde eksipiyan olarak Mannitol, Pre-jelatinize nisasta, Misir nisastasi, Kopovidon, Krospovidon, Talk ve Magnezyum stearat bulunmaktadir. Film-coated tablets containing Empagliflozin and Linagliptin (10mg/5mg, 25mg/5mg) Glyxambi brand It is available in the market with. Mannitol, Pre-gelatinized starch, as excipients in Glyxambi tablets It contains corn starch, Kopovidone, Crospovidone, Talc and Magnesium stearate.

EP 1730131 B1 (Boehringer lngelheim), Empagliflozin molekülünü, kullanimini ve laktoz, misir nisastasi, polivinilpirolidon, magnezyum stearat gibi ile empagliflozin içeren bir tabletin bilesimi açiklanmaktadir. spesifik Empagliflozin kristal formlarini açiklar. boyutunun ve partikül boyutu dagiliminin özellikle çok küçük partiküllerin tabletleme sirasinda yapisarak veya film olusturarak üretilebilirligi olumsuz etkiledigi, öte yandan, çok büyük parçaciklarin çözünme özelliklerini ve dolayisiyla biyoyararlanim üzerinde olumsuz oldugu, ve bu sorunlarin üstesinden gelmek için Empagliflozin'in bilesimdeki partikül boyutu dagiliminin D(90) 1 mikron ve 200 mikron arasinda oldugu açiklanmaktadir. hipromelloz asetat süksinat, povidon PVP K30, SoluplusTM, PEG 6000 veya kopovidon VA64 gibi polimerler ile kati çözelti formunda stabilize edilmis empagliflozin'in amorf kati formlarini açiklar. Empagliflozin'in amorf kati formlarinin çözündürme islemiyle hazirlanmasi için empagliflozin ve polimer metilen klorür ve alkol karisimda çözülmüs, solvent vakumlu buharlastirici veya liyofilizasyon ile uzaklastirilarak amorf empagliflozin elde edilmistir. EP 1730131 B1 (Boehringer lngelheim), Empagliflozin molecule, its use and lactose, empagliflozin containing corn starch, polyvinylpyrrolidone, magnesium stearate etc. The composition of the tablet is described. Describes specific Empagliflozin crystal forms. tableting size and particle size distribution, especially very small particles On the other hand, it adversely affects the manufacturability by sticking or forming a film during on the dissolution properties of very large particles and therefore on bioavailability. negative, and to overcome these problems, Empagliflozin's composition particle size distribution D(90) is between 1 micron and 200 microns is explained. hypromellose acetate succinate, povidone PVP K30, SoluplusTM, PEG 6000 or copovidone Amorphous solid of empagliflozin stabilized in solid solution form with polymers such as VA64 explains the forms. By dissolution of amorphous solid forms of empagliflozin For its preparation, empagliflozin and polymer were dissolved in a mixture of methylene chloride and alcohol, amorphous empagliflozin by removing the solvent by vacuum evaporator or lyophilization. has been obtained.

CN 106692069 A (Foshan), povidon ve kaydirici içeren Empagliflozin kati dispersiyonunu açiklar. dispersiyonlari açiklanmaktadir. Önceki teknik isiginda, iyilestirilmis çözünme profiline sahip, fiziksel ve kimyasal olarak yeterli stabilitesi olan ve ticari ölçekte kullanima uygun ekonomik bir islemle hazirlanan Empagliflozin içeren fiks doz kombinasyonlara ihtiyaç vardir. Ayrica, bulus konusu kompozisyon Empagliflozin'in hem Metformin hem de Linagliptin ile ayri ayri kombine edilebilmesine imkan saglamayan tek bir kompozisyon gelistirilmistir. CN 106692069 A (Foshan), Empagliflozin solid containing povidone and lubricant explains dispersion. dispersions are explained. In the light of the prior art, it has an improved dissolution profile and is physically and chemically sufficient. Empagliflozin is prepared by an economical process that is stable and suitable for use on a commercial scale. Fixed dose combinations containing In addition, the composition subject to the invention Empagliflozin can be combined with both Metformin and Linagliptin separately. A single composition has been developed that does not provide

Bulusun Amaci Teknigin durumunda iyilestirilmis çözünme profiline sahip, fiziksel ve kimyasal olarak yeterli stabilitesi olan ve ticari ölçekte kullanima uygun ekonomik bir islemle hazirlanan Empagliflozin ile ikinci bir etken madde olarak Metformin HCI veya Linagliptin içeren farmasötik bilesimlere olan ihtiyacin yani sira, EP2395968 A1 (Boehringer) basvurusu D90 partikül büyüklügü 5 - 100 mikron arasinda olan Empagliflozin içeren formülasyonlara yönelik oldugundan, farkli partikül boyutlarina sahip Empagliflozin ile ikinci bir etken madde olarak Metformin HCI veya Linagliptin içeren formülasyonlarin hazirlanmasina yönelik prosese ihtiyaç vardir. Mevcut bulus, D90 partikül büyüklügü 100 mikron veya daha fazla olan Empagliflozin ile ikinci bir etken madde olarak Metformin HCI veya Linagliptin içeren farmasötik kompozisyonlara iliskindir. Purpose of the Invention In the state of the art, it has an improved dissolution profile and is physically and chemically Prepared by an economical process with sufficient stability and suitable for use on a commercial scale Containing Metformin HCl or Linagliptin as a second active ingredient with empagliflozin application EP2395968 A1 (Boehringer) as well as the need for pharmaceutical compositions D90 containing Empagliflozin with particle size between 5 - 100 microns Since it is intended for formulations, it can be used with Empagliflozin with different particle sizes. Formulations containing Metformin HCl or Linagliptin as a second active ingredient A process is needed to prepare it. The present invention, D90 particle size 100 Metformin HCl as a second active ingredient with Empagliflozin of microns or more or relates to pharmaceutical compositions containing Linagliptin.

Bulusun açiklamasi Mevcut bulus empagliflozin ile ikinci bir etken madde olarak Metformin HCI veya Linagliptin içeren uygun farmasötik kriterlere sahip oral kompozisyonlara ve bu kompozisyonlarin hazirlanmasina yönelik proseslere iliskindir. Description of the invention The present invention combines empagliflozin with Metformin HCl or Metformin HCl as a second active ingredient. oral compositions containing linagliptin meeting appropriate pharmaceutical criteria and It relates to processes for the preparation of compositions.

Basvuruda kullanilan "Empagliflozin" terimi, Empagliflozin'in serbest bazi, herhangi bir fizyolojik olarak kabul edilebilir tuzu ve kristal formu anlaminda kullanilmistir. The term "Empagliflozin" used in the application refers to the free base of Empagliflozin, any It is used to mean its physiologically acceptable salt and crystal form.

Empagliflozin etkin maddesi Sinif 3 yüksek çözünürlük sinifinda olmasina ragmen permeabilitesi düsük oldugundan çözünürlügü yavastir. Although the active ingredient of empagliflozin is in Class 3 high solubility class, Since its permeability is low, its solubility is slow.

Empagliflozin'in yavas çözünme hizina sahip zayif çözünür bir ilaç oldugundan ilacin çözünme hizi ilacin emilimini dogrudan etkilemektedir. Düsük çözünme hizi, düsük biyoyararlanima yol açar ve ilacin etkinligini etkiler. Önceki teknikte bu sorun dikkate alinarak Empagliflozin içeren çesitli farmasötik bilesimler rapor edilmistir. Açiklanan bilesimlerde empagliflozin kristal formda veya amorf formda bulunur. Kristal form için partikül boyutunun dikkatli bir sekilde kontrol edilmesi gerektigi anlasilmaktadir. Bu amaçla hammaddelerin mikronizasyonu, büyük kayiplara ve düsük verimlere yol açan, atik ve artan maliyetlerle sonuçlanan özel hava akisli ögütme ekipmani gerektirir. Önceki teknikte etkin maddenin çözünürlügü partikül boyutuna göre degisiklik gösterebilir. Since empagliflozin is a poorly soluble drug with a slow dissolution rate, Dissolution rate directly affects the absorption of the drug. low dissolution rate, low It causes bioavailability and affects the effectiveness of the drug. Considering this problem in the prior art, various pharmaceutical products containing Empagliflozin have been prepared. compositions have been reported. In the compositions described, empagliflozin is in crystalline or amorphous form. available in form. Careful control of particle size for crystal form It is understood that it is necessary. For this purpose, micronization of raw materials causes large losses and special airflow grinding leading to low yields, resulting in waste and increased costs requires equipment. In the prior art, the solubility of the active substance may vary depending on the particle size.

Bu nedenle etkin maddenin partikül boyutu çözünürlügü etkilemeyecek sekilde belirli büyüklük araliginda olmali ve maksimum ve minimum partikül boyutu spesifikasyonu belirlenmelidir. Orijinal üründe D90 degeri 20 microndan küçük etkin madde kullanildigi düsünülmektedir. D90 degeri 5 ve 100 pm arasinda olan empagliflozin patentli oldugundan, 5 pm küçük etkin madde kullanilabilmektedir. Ancak bu büyüklükte etkin maddenin kullaniminin üretim açisindan zorluklari olup, biyoesdegerlik açisindan risklidir. For this reason, the particle size of the active substance is determined in a way that does not affect the solubility. must be within the size range and the maximum and minimum particle size specification should be determined. Active ingredient with D90 value less than 20 microns is used in the original product It is considered. Patented empagliflozin with a D90 value between 5 and 100 pm Since it is available, 5 pm small amount of active ingredient can be used. However, at this size effective The use of the substance has difficulties in terms of production and is risky in terms of bioequivalence.

Amorf form çözücünün döner buharlastirici veya liyofilizasyon yoluyla buharlastirilmasi gibi islemlerle kati dispersiyonlar veya kati çözeltiler hazirlanmasini kapsar. Evaporation of amorphous form solvent by rotary evaporator or lyophilization It involves the preparation of solid dispersions or solid solutions by processes such as

Kati dispersiyon prosedürleri endüstriyel ölçekte kullanim için pek uygun degildir. Ayrica endüstriyel ölçekte çözücü olarak metilen klorür kullanildiginda çesitli sakincalar söz konusudur. Önceki teknige ait islemlerle hazirlanan amorf kati dispersiyonlar, ögütme, eleme, diger aktif olmayan bilesenlerle karistirma, tabletler halinde sikistirmadan önce granüllestirme gibi zaman alici ve ekonomik açidan dezavantaji olan islemler gerektirir. Solid dispersion procedures are not well suited for use on an industrial scale. Moreover Various problems arise when methylene chloride is used as a solvent on an industrial scale. is the subject. Amorphous solid dispersions prepared by prior art processes, grinding, sifting, mixing with other inactive ingredients, before compressing into tablets It requires time-consuming and economically disadvantageous processes such as granulation.

Bütün bu zorluklarin üstesinden gelmek için çözünürlük arttirici ajanlarin kullanilmasi ve empagliflozin etkin maddesinin yas granülasyon ile oral farmasötik kompozisyon üretimini saglayan kolay ve ekonomik proses gelistirilmistir. To overcome all these difficulties, the use of solubility enhancing agents and Production of oral pharmaceutical composition of the active ingredient empagliflozin by wet granulation An easy and economical process has been developed that provides

Mevcut bulus ile uygun dissolüsyon profiline sahip bir empagliflozin ile ikinci bir etken madde olarak Metformin HCI veya Linagliptin kompozisyonunun kolay ve ekonomik hazirlanma yöntemi önerilmistir. Etkin maddenin çözünürlügünü attirmak amaciyla Sodyum Hidroksit, Sodyum Bikarbonat, Sodyum Karbonat, Meglumin, Trietanolamin, L- Arjinin, Kalsiyum Karbonat, Magnezyum Karbonat, Trometamin veya bunlarin karisimini içeren bir gruptan seçilen bir bazik ajan ve biyoyararlanimi arttirmak için yüzey aktif madde, tercihen poloksamer kullanilmistir. With the present invention, an empagliflozin with a suitable dissolution profile and a second agent can be used. Easy and economical use of Metformin HCl or Linagliptin composition as ingredients The preparation method is suggested. In order to increase the solubility of the active substance Sodium Hydroxide, Sodium Bicarbonate, Sodium Carbonate, Meglumine, Triethanolamine, L- Arginine, Calcium Carbonate, Magnesium Carbonate, Tromethamine or mixtures thereof a basic agent selected from the group consisting of a surface active agent to increase bioavailability. substance, preferably poloxamer, was used.

Bulusun bir yapilandirmasi Empagliflozin ile ikinci bir etken madde olarak Metformin HCI veya Linagliptin içeren oral farmasötik bir kompozisyon olup, özelligi Empagliflozin D90 partikül büyüklügünün 100 mikron veya daha fazla olmasi, kompozisyonun çözünürlük arttirici bazik ajan içermesidir. One embodiment of the invention is Empagliflozin with Metformin HCl as a second active ingredient. or an oral pharmaceutical composition containing Linagliptin, characterized by Empagliflozin D90 particle size of 100 microns or more, the solubility of the composition It contains a basic enhancing agent.

Kompozisyondaki çözünürlük arttirici bazik ajan agirlik orani tercihen %1-10 arasinda, daha tercihen %1-5 arasindadir. Çözünürlük arttirici bazik ajan olarak tercihen Sodyum Hidroksit, Sodyum Bikarbonat, Sodyum Karbonat, Meglumin, Trietanolamin, L-Arjinin, Kalsiyum Karbonat, Magnezyum Karbonat, Trometamin veya bunlarin karisimini içeren bir gruptan seçilen bir madde kullanilabilir. The weight ratio of the solubility enhancing basic agent in the composition is preferably between 1-10%, more preferably between 1-5%. Preferably Sodium Hydroxide, Sodium Bicarbonate, as solubility enhancing basic agent. Sodium Carbonate, Meglumine, Triethanolamine, L-Arginine, Calcium Carbonate, Magnesium A substance selected from the group consisting of baking soda, tromethamine, or mixtures thereof. can be used.

Bulus konusu farmasötik kompozisyon yüzey aktif madde içerebilir. Kompozisyonda yüzey aktif madde olarak tercihen Poloksamer kullanilir. Poloksamerin Poloksamer 188, 407 gibi çesitli tipleri vardir, tercihen Poloksamer 188 kullanilmaktadir. The pharmaceutical composition of the invention may contain surfactant. in composition Poloxamer is preferably used as a surfactant. Poloxamerin Poloxamer 188, There are various types such as 407, Poloxamer 188 is preferably used.

Kompozisyondaki yüzey aktif maddenin agirlik orani tercihen %0,5-10 arasinda, daha tercihen %0,5-5 arasindadir. The weight ratio of the surfactant in the composition is preferably between 0.5-10%, more preferably between 0.5-5%.

Kompozisyona iliskin en tercih edilen durumda, çözünürlük arttirici bazik ajan Trometamin, yüzey aktif madde olarak Poloksamer kullanilmaktadir. In the most preferred case of the composition, the solubility enhancing basic agent Tromethamine and Poloxamer are used as surfactant.

Bulus konusu kompozisyon direk kompresyon, yas granülasyon, sprey granülasyon veya kuru granülasyon yöntemlerinden herhangi biri ile hazirlanabilmektedir. The composition of the invention can be applied by direct compression, wet granulation, spray granulation or It can be prepared by any of the dry granulation methods.

Bulus konusu oral farmasötik kompozisyon tercihen tablet veya kapsül formundadir. The oral pharmaceutical composition of the invention is preferably in tablet or capsule form.

Bulusun bir diger yapilandirmasi, Empagliflozin ile ikinci bir etken madde olarak Metformin HCI veya Linagliptin içeren oral farmasötik bir kompozisyonun hazirlanmasina yönelik bir proses ile ilgilidir. Another embodiment of the invention is with Empagliflozin as a second active ingredient. For the preparation of an oral pharmaceutical composition containing Metformin HCl or Linagliptin. It is about a process.

Proseste kullanilan Empagliflozin D90 partikül büyüklügünün 100 mikron veya daha fazladir. Empagliflozin D90 particle size used in the process must be 100 microns or more is too much.

Proseste çözünürlük arttirici bazik ajanin ve yüzey aktif maddenin suda çözünmesiyle hazirlanan granülasyon çözeltisi ile Empagliflozinin içinde bulundugu iç faz toz karisimin yas granülasyon veya sprey granülasyon yöntemi ile granüle edilmektedir. In the process, the solubility enhancing basic agent and the surfactant are dissolved in water. The mixture of the prepared granulation solution and the internal phase powder containing Empagliflozin was It is granulated by wet granulation or spray granulation method.

Proseste çözünürlük arttirici ajan olarak tercihen Sodyum Hidroksit, Sodyum Bikarbonat, Sodyum Karbonat, Meglumin, Trietanolamin, L-Arjinin, Kalsiyum Karbonat, Magnezyum Karbonat, Trometamin veya bunlarin karisimini içeren bir gruptan seçilen bir madde kullanilabilir. Sodium Hydroxide, Sodium Bicarbonate, preferably as solubility increasing agent in the process. Sodium Carbonate, Meglumine, Triethanolamine, L-Arginine, Calcium Carbonate, Magnesium A substance selected from the group consisting of baking soda, tromethamine, or mixtures thereof. can be used.

Proseste çözünürlük arttirici bazik ajan agirlik orani tercihen %1-10 arasinda, tercihen Proseste yüzey aktif madde olarak tercihen Poloksamer kullanilir. Poloksamerin Poloksamer 188, 407 gibi çesitli tipleri vardir, tercihen Poloksamer 188 kullanilmaktadir. The weight ratio of basic solubility enhancing agent in the process is preferably between 1-10%, preferably Poloxamer is preferably used as a surfactant in the process. poloxamerin There are various types such as Poloxamer 188, 407, Poloxamer 188 is preferably used.

Proseste yüzey aktif maddenin agirlik orani tercihen %0,5-10 arasinda, daha tercihen Kompozisyona iliskin en tercih edilen durumda, çözünürlük arttirici bazik ajan trometamin, yüzey aktif madde olarak Poloksamer kullanilmaktadir. The weight ratio of the surfactant in the process is preferably between 0.5-10%, more preferably In the most preferred case of the composition, the solubility enhancing basic agent tromethamine and Poloxamer are used as surfactant.

Empagliflozin D90 partikül boyutunun 100 mikrondan fazla olmasina ragmen bu iki madde ile çözünürlük ve biyoyararlanimin artmasi saglanmistir. Although the particle size of empagliflozin D90 is more than 100 microns, these two Solubility and bioavailability increased with the substance.

Böylece gelistirilen yöntem ile mikronize empagliflozin kullanilmadan etkin maddenin çözünürlügü arttirilmistir. Thus, with the developed method, the active substance is extracted without using micronized empagliflozin. The resolution has been increased.

Bulus konusu Empagliflozin ve ikinci bir etken madde olarak Metformin Hidroklorür veya Linagliptin içeren kompozisyon tercihen asagidaki prosese göre hazirlanabilir: a. Empagliflozin ve ikinci bir etken madde olarak Metformin Hidroklorür veya Linagliptin ile yardimci maddelerin karistirilarak iç faz toz karisimin hazirlanmasi, b. Saf su, poloksamer ve trometamin karistirilarak granülasyon çözeltisinin hazirlanmasi, 0. Iç faz toz karisimin granülasyon çözeltisi ile yas granülasyon veya sprey granülasyon yöntemi ile granüle edilmesi, d. Elde edilen granüllerin kurutulmasi, e. Kuruyan granüllerin elenmesi, f. Diger yardimci maddeler “e” asamasi sonucu elde edilen granüle eklenmesi ve karistirilmasi, g. Kaydiricinin eklenmesi ve karistirilmasi. The subject of the invention is Empagliflozin and Metformin Hydrochloride or Metformin Hydrochloride as a second active ingredient. The linagliptin-containing composition can preferably be prepared according to the following process: a. Empagliflozin and Metformin Hydrochloride or Linagliptin as a second active ingredient Preparation of the inner phase powder mixture by mixing auxiliary materials with b. Preparation of granulation solution by mixing pure water, poloxamer and tromethamine, 0. Wet granulation or spray granulation with granulation solution of the inner phase powder mixture granulating by method, D. Drying the obtained granules, to. Sifting the dried granules, f. Other auxiliary substances are added to the granule obtained as a result of step "e" and mixing, g. Add slider and mix.

Bulusun bir yapilandirmasi olan Empagliflozin ve Metformin Hidroklorür içeren proses tercihen asagidaki adimlari içerir; a. Empagliflozin, Metformin Hidroklorür, dolgu ve/veya seyreltici, ve baglayici ajanlarin karistirilarak iç faz toz karisimin hazirlanmasi, b. Saf su, poloksamer ve trometamin karistirilarak granülasyon çözeltisinin hazirlanmasi, 0. Iç faz toz karisimin granülasyon çözeltisi ile yas granülasyon veya sprey granülasyon yöntemi ile granüle edilmesi, d. Elde edilen granüllerin kurutulmasi, e. Kuruyan granüllerin elenmesi, f. Diger yardimci maddeler “e” asamasi sonucu elde edilen granüle eklenmesi ve karistirilmasi, g. Kaydiricinin eklenmesi ve karistirilmasi. Process involving Empagliflozin and Metformin Hydrochloride, an embodiment of the invention preferably includes the following steps; a. Empagliflozin, Metformin Hydrochloride, filler and/or diluent, and binding agents Preparation of the internal phase powder mixture by mixing, b. Preparation of granulation solution by mixing pure water, poloxamer and tromethamine, 0. Wet granulation or spray granulation with granulation solution of the inner phase powder mixture granulating by method, D. Drying the obtained granules, to. Sifting the dried granules, f. Other auxiliary substances are added to the granule obtained as a result of step "e" and mixing, g. Add slider and mix.

Bulusun diger bir yapilandirmasi olan Empagliflozin ve Linagliptin içeren proses tercihen asagidaki adimlari içerir; a. Empagliflozin, Metformin Hidroklorür, dolqu ve/veya seyreltici, ve baglayici ajanlarin karistirilarak iç faz toz karisimin hazirlanmasi, b. Saf su, poloksamer ve trometamin karistirilarak granülasyon çözeltisinin hazirlanmasi, 0. Iç faz toz karisimin granülasyon çözeltisi ile yas granülasyon veya sprey granülasyon yöntemi ile granüle edilmesi, d. Elde edilen granüllerin kurutulmasi, e. Kuruyan granüllerin elenmesi, f. Diger yardimci maddeler “e” asamasi sonucu elde edilen granüle eklenmesi ve karistirilmasi, g. Kaydiricinin eklenmesi ve karistirilmasi. Another embodiment of the invention, the process comprising Empagliflozin and Linagliptin, is preferably It includes the following steps; a. Empagliflozin, Metformin Hydrochloride, filler and/or diluent, and binding agents Preparation of the internal phase powder mixture by mixing, b. Preparation of granulation solution by mixing pure water, poloxamer and tromethamine, 0. Wet granulation or spray granulation with granulation solution of the inner phase powder mixture granulating by method, D. Drying the obtained granules, to. Sifting the dried granules, f. Other auxiliary substances are added to the granule obtained as a result of step "e" and mixing, g. Add slider and mix.

Mevcut bulus ile uygun dissolüsyon profiline sahip bir empagliflozin ile ikinci bir etken madde olarak Metformin Hidroklorür veya Linagliptin içeren oral farmasötik kompozisyonlarinin hazirlanmasina iliskin proseste dolgu maddesi ve seyreltici olarak mannitol ve misir nisastasi kullanilabilir. Kompozisyon ayrica dagitici olarak krospovidon ve prejelatinize nisasta, lubrikan olarak talk, baglayici olarak kopovidon, kaydirici olarak magnezyum stearat içerebilir. Önerilen oral farmasötik kompozisyon direk kompresyon, kuru granülasyon, yas granülasyon veya sprey granülasyon yöntemleri ile üretilebilir. Örnekler Asagidaki örnekler bulusun daha iyi açiklanmasi amaciyla verilmis olup, bulusun kapsamini sinirlandirmamaktadir. 1-3 arasindaki örnekler Empagliflozin ve Metformin Hidroklorür içeren kompozsiyonlar ile ilgili olup, 4-6 arasindaki örnekler Empagliflozin ve Linagliptin içeren kompozisyonlar ile ilgilidir. With the present invention, an empagliflozin with a suitable dissolution profile and a second agent can be used. oral pharmaceutical containing Metformin Hydrochloride or Linagliptin as ingredients as filler and diluent in the process of preparation of compositions Mannitol and corn starch can be used. The composition also includes crospovidone as dispersant and pregelatinized starch, talc as lubricant, copovidone as binder, lubricant May contain magnesium stearate. Recommended oral pharmaceutical composition: direct compression, dry granulation, mourning It can be produced by granulation or spray granulation methods. Examples The examples below are given to better explain the invention. It does not limit its scope. Examples 1-3 Empagliflozin and Metformin Examples 4-6 relate to compositions containing hydrochlorides, Empagliflozin and It concerns compositions containing linagliptin.

Bulus konusu kompozisyonun gelistirilme sürecinde önce asagida belirtilen Formül 1 hazirlanmis ve dissolüsyon testi ile çözünme hizlari kontrol edilmistir. During the development process of the composition subject to the invention, Formula 1 specified below was first used. were prepared and dissolution rates were checked by dissolution test.

Birim Formül Hammadde Adi mg/ tablet % Empagliflozin* 12,500 1,01 Hidroksipropil Selüloz 50,000 4,03 Kolloidal Silikon Dioksit 8,000 0,64 Magnezyum Stearat 12,000 0,97 Saf Su k.m. - Film Kaplama 20,000 FILM TABLET AGIRLIGI 1260,000 *Partikül boyutu D90> 100 mikron Empagliflozin kullanilmistir. Üretim Yöntemi: 1- Empagliflozin, Metformin Hidroklorür, Misir Nisastasi ve Hidroksipropil Selüloz karistirilir. 2-Saf su ile 1 numaradaki karisim granül edilir. 3-Granüller kurutulur. 4-Kuruyan granüller elenir. Unit Formula Raw Material Name mg/tablet% Empagliflozin* 12,500 1.01 Hydroxypropyl Cellulose 50,000 4.03 Colloidal Silicon Dioxide 8,000 0.64 Magnesium Stearate 12,000 0.97 Pure Water k.m. - Film Coating 20,000 FILM TABLET WEIGHT 1260,000 *Empagliflozin with particle size D90> 100 microns was used. Production Method: 1- Empagliflozin, Metformin Hydrochloride, Corn Starch and Hydroxypropyl Cellulose is mixed. 2-The mixture number 1 is granulated with pure water. 3-Granules are dried. 4-Drying granules are sieved.

-Kolloidal Silikon Dioksit 4 numarali elenmis granüle eklenir ve karistirilir. 6-Magnezyum Stearat eklenir ve karistirilir. 7-Tablet baski makinesinde 6 numarali karisim basilir. 8-Spesifikasyonlara uygun olarak tabletler kaplanir. Çözünme hizi metodu asagidadir. ÇÖZÜNME HIZI METODU Ekipman Agilent DS708 Dissolusyon Cihazi Aparat Paddle Rotasyon Hizi 50 rpm Tampon pH 6,8 Fosfat Tamponu Tampon Hacmi 900 ml Sicaklik 37°C Formül 1'e iliskin Empagliflozin Çözünme Hizi Analiz Sonuçlari asagidadir. -Colloidal Silicon Dioxide is added to the sieved granule number 4 and mixed. 6-Magnesium Stearate is added and mixed. 7- Mixture number 6 is printed on the tablet press machine. 8-Tablets are coated in accordance with the specifications. The dissolution rate method is as follows. DISSOLVATION RATE METHOD Equipment Agilent DS708 Dissolution Device Apparatus Paddle Rotation Speed 50 rpm Buffer pH 6.8 Phosphate Buffer Buffer Volume 900 ml Temperature 37°C Empagliflozin Dissolution Rate Analysis Results for Formula 1 are below.

EMPAGLIFLOZIN Benzerlik Faktörü f2: 24 Formül 1'in referans ürün ile karsilastirmali Empagliflozin çözünme hizi analiz sonuç grafigi asagidadir. EMPAGLIFLOZIN Similarity Factor f2: 24 Empagliflozin dissolution rate analysis result graph compared to the reference product of Formula 1 below.

Karsilastirmali Çözünme Hizi Profili U' -O-Referans Ürün @sf-?Test Ürün Zaman [dk]Formül 1'e iliskin Metformin Hidroklorür Çözünme Hizi Analiz Sonuçlari asagidadir. Comparative Dissolution Rate Profile U' -O-Reference Product @sf-?Test Product Time [min]Metformin Hydrochloride Dissolution Rate Analysis Results for Formula 1 are below.

METFORMIN HIDROKLORÜR Benzerlik Faktörü f2: 59 Formül 1'in referans ürün ile karsilastirmali Metformin Hidroklorür çözünme hizi analiz sonuç grafigi asagidadir. METFORMIN HYDROCHLORIDE Similarity Factor f2: 59 Metformin Hydrochloride dissolution rate analysis result in comparison with the reference product of Formula 1 The graph is below.

Karsilastirmali Çözünme Hizi Profili 100 - ,. ` &W _ Zaman (dk) Bulus konusu kompozisyonun gelistirilme sürecinde önce asagida belirtilen Formül 2 hazirlanmis ve dissolüsyon testi ile çözünme hizlari kontrol edilmistir. Comparative Dissolution Rate Profile one hundred - ,. ` &W _ Time (min) During the development process of the composition subject to the invention, Formula 2 specified below was first used. were prepared and dissolution rates were checked by dissolution test.

Birim Formül Hammadde Adi mg/ tablet % Empagliflozin* 12,500 1,01 Misir Nisastasi 107,500 8,67 Hidroksipropil Selüloz 50,000 4,03 Hidroksipropil Selüloz 50,000 Kolloidal Silikon Dioksit 8,000 0,64 Magnezyum Stearat 12,000 0,97 Saf Su k.m. - Film Kaplama 20,000 FILM TABLET AGIRLIGI 1260,000 *Partikül boyutu D90> 100 mikron Empagliflozin kullanilmistir. Üretim Yöntemi: 1- Empagliflozin, Metformin Hidroklorür, Misir Nisastasi ve Hidroksipropil Selüloz karistirilir. 2-Saf su ile 1 numaradaki karisim granül edilir. 3-Granüller kurutulur. 4-Kuruyan granüller elenir. Unit Formula Raw Material Name mg/tablet% Empagliflozin* 12,500 1.01 Corn Starch 107,500 8.67 Hydroxypropyl Cellulose 50,000 4.03 Hydroxypropyl Cellulose 50,000 Colloidal Silicon Dioxide 8,000 0.64 Magnesium Stearate 12,000 0.97 Pure Water k.m. - Film Coating 20,000 FILM TABLET WEIGHT 1260,000 *Empagliflozin with particle size D90> 100 microns was used. Production Method: 1- Empagliflozin, Metformin Hydrochloride, Corn Starch and Hydroxypropyl Cellulose is mixed. 2-The mixture number 1 is granulated with pure water. 3-Granules are dried. 4-Drying granules are sieved.

- Hidroksipropil Selüloz(Düsük Sübstitüsyonlu) ve Kolloidal Silikon Dioksit 4 numarali elenmis granüle eklenir ve karistirilir. 6-Magnezyum Stearat eklenir ve karistirilir. 7-Tablet baski makinesinde 6 numarali karisim basilir. 8-Spesifikasyonlara uygun olarak tabletler kaplanir. - Hydroxypropyl Cellulose (Low Substitution) and Colloidal Silicon Dioxide number 4 It is added to the sieved granule and mixed. 6-Magnesium Stearate is added and mixed. 7- Mixture number 6 is printed on the tablet press machine. 8-Tablets are coated in accordance with the specifications.

Formül 2'ye iliskin Empagliflozin Çözünme Hizi Analiz Sonuçlari asagidadir. Empagliflozin Dissolution Rate Analysis Results for Formula 2 are below.

EMPAGLIFLOZIN Benzerlik Faktörü f2: 27 Formül 2'nin referans ürün ile karsilastirmali Empagliflozin çözünme hizi analiz sonuç grafigi asagidadir. EMPAGLIFLOZIN Similarity Factor f2: 27 Empagliflozin dissolution rate analysis result in comparison with the reference product of Formula 2 The graph is below.

Karsilastirmali Çözünme Hizi Profili E _ i n mese” ww ww h" ”E Q -O-Referans Ürün MçryTest Ürün Zaman [dk] Formül 2'ye iliskin Metformin Hidroklorür Çözünme Hizi Analiz Sonuçlari asagidadir. Comparative Dissolution Rate Profile E _ i n mese” ww ww h” ”E Q -O-Reference Product MçryTest Product Time [min] Metformin Hydrochloride Dissolution Rate Analysis Results for Formula 2 are below.

METFORMIN HIDROKLORÜR Benzerlik Faktörü f2: 67 Formül 2'in referans ürün ile karsilastirmali Metformin Hidroklorür çözünme hizi analiz sonuç grafigi asagidadir. METFORMIN HYDROCHLORIDE Similarity Factor f2: 67 Comparative Metformin Hydrochloride dissolution rate analysis with reference product of Formula 2 The result graph is below.

Karsilastirmali çözünme Hizi Profili 1%' ?ISI . E 100 100 99 Zaman [dk] Bulus konusu kompozisyonun gelistirilme sürecinde önce asagida belirtilen Formül 3 hazirlanmis ve dissolüsyon testi ile çözünme hizlari kontrol edilmistir. Comparative dissolution rate profile 1%' ?TEMP . TO 100 100 99 Time [min] During the development process of the composition subject to the invention, Formula 3 mentioned below was first used. were prepared and dissolution rates were checked by dissolution test.

Birim Formül Hammadde Adi mg/ tablet % Empagliflozin* 12,500 1,01 Misir Nisastasi 47,500 3,83 Trometamin 50,000 4,03 Hidroksipropil Selüloz 50,000 4,03 Hidroksipropil Selüloz 50,000 Kolloidal Silikon Dioksit 8,000 0,64 Magnezyum Stearat 12,000 0,97 Saf Su k.m. - Film Kaplama 20,000 FILM TABLET AGIRLIGI 1260,000 *Partikül boyutu D90> 100 mikron Empagliflozin kullanilmistir. Üretim Yöntemi: 1- Empagliflozin, Metformin Hidroklorür, Misir Nisastasi ve Hidroksipropil Selüloz karistirilir. 2- Saf suda Poloksamer ve Trometamin çözülür. 1 numaradaki karisim bu çözelti ile granül edilir. 3-Granüller kurutulur. 4-Kuruyan granüller elenir. Unit Formula Raw Material Name mg/tablet% Empagliflozin* 12,500 1.01 Corn Starch 47,500 3.83 Tromethamine 50,000 4.03 Hydroxypropyl Cellulose 50,000 4.03 Hydroxypropyl Cellulose 50,000 Colloidal Silicon Dioxide 8,000 0.64 Magnesium Stearate 12,000 0.97 Pure Water k.m. - Film Coating 20,000 FILM TABLET WEIGHT 1260,000 *Empagliflozin with particle size D90> 100 microns was used. Production Method: 1- Empagliflozin, Metformin Hydrochloride, Corn Starch and Hydroxypropyl Cellulose is mixed. 2- Poloxamer and Tromethamine are dissolved in pure water. The mixture in number 1 is mixed with this solution. It is granulated. 3-Granules are dried. 4-Drying granules are sieved.

Formül 3'e iliskin Empagliflozin Çözünme Hizi Analiz Sonuçlari asagidadir. Empagliflozin Dissolution Rate Analysis Results for Formula 3 are below.

EMPAGLIFLOZIN Test Ürün 29 65 83 90 Benzerlik Faktörü f2: 66 Formül 3'ün referans ürün ile karsilastirmali Empagliflozin çözünme hizi analiz sonuç grafigi asagidadir. Çüzünen Miktar[%] Karsilastirmali çözünme Hizi Profili *Referans Ü run W# *ni-*TE 51: Ü rLJn Formül 3'e iliskin Metformin Hidroklorür Çözünme Hizi Analiz Sonuçlari asagidadir. EMPAGLIFLOZIN Test Product 29 65 83 90 Similarity Factor f2: 66 Empagliflozin dissolution rate analysis result graph compared to the reference product of Formula 3 below. Dissolved Amount [%] Comparative dissolution rate profile *Reference Product W# *ni-*TE 51: Ü rLJn Metformin Hydrochloride Dissolution Rate Analysis Results for Formula 3 are below.

METFORMIN HIDROKLORÜR Benzerlik Faktörü f2: 60 Formül 3'ün referans ürün ile karsilastirmali Metformin Hidroklorür çözünme hizi analiz sonuç grafigi asagidadir. METFORMIN HYDROCHLORIDE Similarity Factor f2: 60 Comparative Metformin Hydrochloride dissolution rate analysis with reference product of Formula 3 The result graph is below.

Karsilastirmali Çözünme Hizi Profili 123 i'm 1%; :i ?S . > Örnek 4 Gelistirme asamasinda çalisilan formül 4 asagidadir. Comparative Dissolution Rate Profile 123 i'm 1%; :I ?S . > Example 4 Below is the formula 4 studied during the development phase.

Birim Formül Hammadde Adi mg/ tablet % Empagliflozin* 25,000 16,67 Linagliptin 5,000 3,33 Mannitol 55,000 36,67 Prejelatinize Nisasta 25,000 16,67 Misir Nisastasi 20,000 13,33 Kopovidon 3,000 2,00 Krospovidon 3,000 2,00 Magnezyum Stearat 4,000 2,66 Saf Su k.m. k.m. Unit Formula Raw Material Name mg/tablet% Empagliflozin* 25,000 16.67 Linagliptin 5,000 3.33 Mannitol 55,000 36.67 Pregelatinized Starch 25,000 16.67 Corn Starch 20,000 13.33 Kopovidone 3,000 2.00 Crospovidone 3,000 2.00 Magnesium Stearate 4,000 2.66 Pure Water k.m. k.m.

Film Kaplama Maddesi 5,000 - *Partikül boyutu D90> 100 mikron Empagliflozin kullanilmistir. Üretim Yöntemi: 1- Empagliflozin, Linagliptin, Mannitol, Misir Nisastasi ve Kopovidon karistirilir. 2-Saf su ile 1 numaradaki karisim granül edilir. 3-Granüller kurutulur. 4-Kuruyan granüller elenir. 5-Talk, Prejelatinize Nisasta ve Krospovidon 4 numarali elenmis granüle eklenir ve karistirilir. 6-Magnezyum Stearat eklenir ve karistirilir. 7-Tablet baski makinesinde 6 numarali karisim basilir. 8-Basilan tabletler kaplanir. Film Coating Agent 5,000 - *Empagliflozin with particle size D90> 100 microns was used. Production Method: 1- Empagliflozin, Linagliptin, Mannitol, Corn Starch and Kopovidone are mixed. 2-The mixture number 1 is granulated with pure water. 3-Granules are dried. 4-Drying granules are sieved. 5-Talc, Pregelatinized Starch and Crospovidone are added to the sieved granule number 4 and is mixed. 6-Magnesium Stearate is added and mixed. 7- Mixture number 6 is printed on the tablet press machine. 8-The pressed tablets are coated.

Formül 4'e iliskin Empagliflozin Çözünme Hizi Analiz Sonuçlari asagidadir. Empagliflozin Dissolution Rate Analysis Results for Formula 4 are below.

EMPAGLIFLOZIN Benzerlik Faktörü f2: 26 Formül 4'ün referans ürün ile karsilastirmali Empagliflozin çözünme hizi analiz sonuç grafigi asagidadir. EMPAGLIFLOZIN Similarity Factor f2: 26 Empagliflozin dissolution rate analysis result in comparison with the reference product of Formula 4 The graph is below.

Karsilastirmali çözünme Hizi Profili 95 96 96 m .1 .vw ' U' +Referans Ürun mr-;W'ATest Ürun Zaman [dk] Formül 4'e iliskin Linagliptin Çözünme Hizi Analiz Sonuçlari asagidadir. Comparative dissolution rate profile 95 96 96 m .1 .vw ' U' +Reference Product mr-;W'ATest Product Time [min] Linagliptin Dissolution Rate Analysis Results for Formula 4 are below.

LINAGLIPTIN Benzerlik Faktörü f2: 77 Formül 4'ün referans ürün ile karsilastirmali Linagliptin çözünme hizi analiz sonuç grafigi asagidadir. LINAGLIPTIN Similarity Factor f2: 77 Linagliptin dissolution rate analysis result graph compared to the reference product of Formula 4 below.

Karsilastirmali Çözünme Hizi Profili 100 _ .,.-- Ir” 1.: Max; Zaman [dk] Gelistirme asamasinda çalisilan formül 5 asagidadir. Comparative Dissolution Rate Profile 100 _ .,.-- Ir” 1st: Max; Time [min] The formula 5 studied during the development phase is below.

Birim Formül Hammadde Adi mg/ tablet % Empagliflozin* 25,000 16,67 Linagliptin 5,000 3,33 Mannitol 52,000 34,67 Prejelatinize Nisasta 25,000 16,67 Misir Nisastasi 20,000 13,33 Kopovidon 3,000 2,00 Krospovidon 6,000 4,00 Magnezyum Stearat 4,000 2,66 Saf Su k.m. k.m. Unit Formula Raw Material Name mg/tablet% Empagliflozin* 25,000 16.67 Linagliptin 5,000 3.33 Mannitol 52,000 34.67 Pregelatinized Starch 25,000 16.67 Corn Starch 20,000 13.33 Kopovidone 3,000 2.00 Crospovidone 6,000 4.00 Magnesium Stearate 4,000 2.66 Pure Water k.m. k.m.

Film Kaplama Maddesi 5,000 - *Partikül boyutu D90> 100 mikron Empagliflozin kullanilmistir. Üretim Yöntemi: 1- Empagliflozin, Linagliptin, Mannitol, Misir Nisastasi ve Kopovidon karistirilir. 2-Saf su ile 1 numaradaki karisim granül edilir. 3-Granüller kurutulur. 4-Kuruyan granüller elenir. Film Coating Agent 5,000 - *Empagliflozin with particle size D90> 100 microns was used. Production Method: 1- Empagliflozin, Linagliptin, Mannitol, Corn Starch and Kopovidone are mixed. 2-The mixture number 1 is granulated with pure water. 3-Granules are dried. 4-Drying granules are sieved.

-Talk, Prejelatinize Nisasta ve Krospovidon 4 numarali elenmis granüle eklenir ve karistirilir. 6-Magnezyum Stearat eklenir ve karistirilir. 7-Tablet baski makinesinde 6 numarali karisim basilir. 8-Basilan tabletler kaplanir. -Talc, Pregelatinized Starch and Crospovidone are added to the sieved granule number 4 and is mixed. 6-Magnesium Stearate is added and mixed. 7- Mixture number 6 is printed on the tablet press machine. 8-The pressed tablets are coated.

Formül 5'e iliskin Empagliflozin Çözünme Hizi Analiz Sonuçlari asagidadir. Empagliflozin Dissolution Rate Analysis Results for Formula 5 are below.

EMPAGLIFLOZIN Benzerlik Faktörü f2: 26 Formül 5'in referans ürün ile karsilastirmali Empagliflozin çözünme hizi analiz sonuç grafigi asagidadir. EMPAGLIFLOZIN Similarity Factor f2: 26 Empagliflozin dissolution rate analysis result in comparison with the reference product of Formula 5 The graph is below.

Karsilastirmali Çözünme Hizi Profili t.)- +Referan5 Ürun --Test Ürun Zaman [dk] Formül 5,e iliskin Linagliptin Çözünme Hizi Analiz Sonuçlari asagidadir. Comparative Dissolution Rate Profile t.)- +Reference5 Product --Test Product Time [min] Linagliptin Dissolution Rate Analysis Results for Formula 5 are below.

LINAGLIPTIN Benzerlik Faktörü f2: 67 Formül 5'in referans ürün ile karsilastirmali Linagliptin çözünme hizi analiz sonuç grafigi asagidadir. LINAGLIPTIN Similarity Factor f2: 67 Linagliptin dissolution rate analysis result graph compared to the reference product of Formula 5 below.

Karsilastirmali Çözünme Hizi Profili 100 4-!- _I I E .5 -û-Referans Ürun .il-Test Ürun a20D I' i i i i i i i i i Zaman (dk) Gelistirme asamasinda çalisilan formül 6 asagidadir. Comparative Dissolution Rate Profile 100 4-!- _I I E .5 -û-Reference Product .il-Test Product a20D I' i i i i i i i i Time (min) Below is the formula 6 studied during the development phase.

Birim Formül Hammadde Adi mg/ tablet % Empagliflozin* 25,000 16,67 Linagliptin 5,000 3,33 Mannitol 47,000 31,33 Prejelatinize Nisasta 25,000 16,67 Misir Nisastasi 17,000 11,34 Kopovidon 3,000 2,00 Krospovidon 6,000 4,00 Trometamin 6,000 4,00 Magnezyum Stearat 4,000 2,66 Film Kaplama Maddesi 5,000 - *Partikül boyutu D90> 100 mikron Empagliflozin kullanilmistir. Üretim Yöntemi: 1- Empagliflozin, Linagliptin, Mannitol, Misir Nisastasi ve Kopovidon karistirilir. 2-Saf suda Poloksamer ve Trometamin çözülerek granülasyon çözeltisi hazirlanir. Bu çözelti ile granülasyon yapilir. 3-Granüller kurutulur. 4-Kuruyan granüller elenir. Unit Formula Raw Material Name mg/tablet% Empagliflozin* 25,000 16.67 Linagliptin 5,000 3.33 Mannitol 47,000 31.33 Pregelatinized Starch 25,000 16.67 Corn Starch 17,000 11.34 Kopovidone 3,000 2.00 Crospovidone 6,000 4.00 Tromethamine 6,000 4.00 Magnesium Stearate 4,000 2.66 Film Coating Agent 5,000 - *Empagliflozin with particle size D90> 100 microns was used. Production Method: 1- Empagliflozin, Linagliptin, Mannitol, Corn Starch and Kopovidone are mixed. 2-Granulation solution is prepared by dissolving Poloxamer and Tromethamine in pure water. This Granulation is done with the solution. 3-Granules are dried. 4-Drying granules are sieved.

Formül 6'ya iliskin Empagliflozin Çözünme Hizi Analiz Sonuçlari asagidadir. Empagliflozin Dissolution Rate Analysis Results for Formula 6 are below.

EMPAGLIFLOZIN Benzerlik Faktörü f2: 74 Formül 6'nin referans ürün ile karsilastirmali Empagliflozin çözünme hizi analiz sonuç grafigi asagidadir. EMPAGLIFLOZIN Similarity Factor f2: 74 Empagliflozin dissolution rate analysis result in comparison with the reference product of Formula 6 The graph is below.

Karsilastirmali Çözünme Hizi Profili 100 - .M ,1 .7 F y 4;,, .r 3' U' +Referans Ürün &basta-Test Ürün Zaman [dk] Formül 6'ya iliskin Linagliptin Çözünme Hizi Analiz Sonuçlari asagidadir. Comparative Dissolution Rate Profile 100 - .M ,1 .7 F y 4;,, .r 3' U' +Reference Product &basta-Test Product Time [min] Linagliptin Dissolution Rate Analysis Results for Formula 6 are below.

LINAGLIPTIN Benzerlik Faktörü f2: 69 Formül 6'nin referans ürün ile karsilastirmali Linagliptin çözünme hizi analiz sonuç grafigi asagidadir. LINAGLIPTIN Similarity Factor f2: 69 Linagliptin dissolution rate analysis result graph compared to the reference product of Formula 6 below.

Karsilastirmali Çözünme Hizi Profili 100 Sa. :5. “F" ::at .g -û-Referans Ürün m'îêwiTest Ürün Zaman [dk] Sonuç olarak, dissolüsyon profili analiz sonuçlarinda görüldügü üzere Trometamin ve Poloksamer kullanilmasi etkin maddenin çözünürlügünü arttirmistir. Dissolüsyon analizi için referans ürün ile benzerlik faktörü f2 üzerinden degerlendirme yapildiginda çözünme hizi bakimindan yüksek benzerlik elde edilmistir. Comparative Dissolution Rate Profile 100 Hrs. :5. “F" ::at .g -û-Reference Product m'îêwiTest Product Time [min] As a result, as seen in the dissolution profile analysis results, Tromethamine and Using poloxamer increased the solubility of the active substance. Dissolution analysis When evaluated based on the similarity factor f2 with the reference product, the dissolution High similarity was achieved in terms of speed.

Mevcut bulusta belirtilmis olan çözünürlük arttirici ajanlar kullanilarak üretimi yapilmis üründe etkin madde Empagliflozinin çözünürlügü arttirmistir. Dissolüsyon analizi için referans ürün ile benzerlik faktörü f2 üzerinden degerlendirme yapildiginda çözünme hizi bakimindan yüksek benzerlik elde edilmistir. It was produced using the solubility enhancing agents specified in the present invention. The active ingredient in the product, Empagliflozin, increased the solubility. For dissolution analysis Dissolution rate when evaluated based on the similarity factor f2 with the reference product High similarity was achieved in terms of

Partikül boyutu D90>100 mikron olan Empagliflozinin, çözünürlük arttirici ajanlar kullanilarak üretilen oral farmasötik form bitmis ürününün, orijinal ürüne benzer dissolüsyon profili elde edilmesi ilk olarak bu bulusta kanitlanmistir. Empagliflozin, whose particle size D90>100 microns, is used as solubility enhancing agents. The finished product of oral pharmaceutical form produced using Obtaining a dissolution profile was first proven in this invention.

Yukaridaki yapilan çalismada birim formüle göre kullanilan çözünürlük arttirici bazik ajanin çekirdek tablete agirlik olarak orani 1-10 arasinda, tercihen %1-5 arasinda olmasidir. Bu degerlerin disinda uygun dissolüsyon profili elde edilememektedir. In the study above, the solubility enhancer used according to the unit formula was basic The weight ratio of the agent to the core tablet is between 1-10%, preferably between 1-5%. is to be. Apart from these values, the appropriate dissolution profile cannot be obtained.

Claims

STEMS

1. It is an oral pharmaceutical composition containing Empagliflozin and Metformin Hydrochloride or Linagliptin as a second active ingredient, and its feature is that the particle size of Empagliflozin D90 is 100 microns or more and the composition contains a solubility-enhancing basic agent.

2. A pharmaceutical composition according to claim 1, characterized in that the weight ratio of the solubility-enhancing basic agent in the composition is between 1-10%, preferably between 1-5%.

3. A pharmaceutical composition according to any one of the preceding claims, characterized in that the solubility enhancing basic agent is selected from the group consisting of Sodium Hydroxide, Sodium Bicarbonate, Sodium Carbonate, Meglumine, Triethanolamine, L-Arginine, Calcium Carbonate, Magnesium Carbonate, Tromethamine or mixtures thereof.

4. A pharmaceutical composition according to any one of the preceding claims, characterized in that

5. A pharmaceutical composition according to claim 4, characterized in that it contains Poloxamer as a surfactant.

6. A pharmaceutical composition according to claim 4 or 5, characterized in that the weight fraction of the surfactant in the composition is between 0.5-10%, preferably between 0.5-5%.

7. A pharmaceutical composition according to any one of the preceding claims, characterized in that it contains Tromethamine as a solubility-enhancing basic agent and Poloxamer as a surfactant.

8. A pharmaceutical composition according to any of the previous claims, characterized in that it is prepared by dry mixing, wet granulation, dry granulation or spray granulation method.

9. A pharmaceutical composition according to any of the preceding claims, characterized in that the composition is in tablet or capsule form.

10. A process for the preparation of an oral pharmaceutical composition containing Empagliflozin and Metformin Hydrochloride or Linagliptin as a second active ingredient, characterized in that -the particle size of Empagliflozin used in the process is d90>100 microns or more, -the solubility enhancing basic agent and the surfactant are present in water It is the granulation of the granulation solution prepared by dissolving the internal phase powder mixture containing Empagliflozin by wet granulation or spray granulation method.

11. A process according to claim 10, characterized in that the solubility enhancing basic agent is selected from a group consisting of Sodium Hydroxide, Sodium Bicarbonate, Sodium Carbonate, Meglumine, Triethanolamine, L-Arginine, Calcium Carbonate, Magnesium Carbonate, Tromethamine or mixtures thereof.

12. A process according to claim 10 or 11, characterized in that it contains Poloxamer as a surfactant.

13. It is a process according to any one of the claims 10-11, and its feature is; a. Preparation of the internal phase powder mixture by mixing empagliflozin and Metformin Hydrochloride or Linagliptin as a second active ingredient and auxiliary substances, b. Preparation of granulation solution by mixing pure water, poloxamer and tromethamine,

0. Granulating the inner phase powder mixture with granulation solution by wet granulation or spray granulation method, d. Drying the resulting granules, e. Sifting of dried granules, f. Adding and mixing other auxiliary substances to the granule obtained as a result of step "e", g. Add slider and mix.