TR2022009903A2

TR2022009903A2 - A FORMULATION OF EMPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE

Info

Publication number: TR2022009903A2
Application number: TR2022/009903
Authority: TR
Inventors: Guler Tolga; Sunel Fati̇h; Pehli̇van Akalin Nur; Armut Merve
Original assignee: Sanovel İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇
Filing date: 2022-06-15
Publication date: 2023-12-21

Abstract

Mevcut buluş, empagliflozin ve metformin hidroklorür ve en az bir bağlayıcı içeren intragranüler bir kompozisyon içeren film kaplı bir tablet ile ilgili olup, intragranüler kompozisyon alkol içeren bir solvent kullanılarak yaş granülasyon yoluyla elde edilir. Proses, basit, hızlı, maliyet etkin, zaman kazandıran ve endüstriyel olarak uygun bir prosestir.The present invention relates to a film-coated tablet comprising an intragranular composition comprising empagliflozin and metformin hydrochloride and at least one binder, the intragranular composition being obtained by wet granulation using an alcohol-containing solvent. The process is simple, fast, cost-effective, time-saving and industrially suitable.

Description

TARIFNAME BIR EMPAGLIFLOZIN VE METFORMIN HIDROKLORÜR FORMÜLASYONU Bulusun Alani Mevcut bulus, empagliflozin ve metformin hidroklorür ve en az bir baglayici içeren intragranüler bir kompozisyon içeren bir film kapli tablet ile ilgili olup, burada intragranüler kompozisyon, alkol içeren bir solvent kullanilarak yas granülasyon yoluyla elde edilir. Proses basit, hizli, maliyet etkin, zaman kazandiran ve endüstriyel olarak uygun bir prosestir. Bulusun Arka Plani Diabetes mellitus, bozulmus sekresyon, azalmis insülin aktivitesi veya her iki faktörün bir kombinasyonu nedeniyle insülin aksiyonunun azaldigi veya hiç bulunmadigi bir grup karbonhidrat metabolizmasi bozuklugudur. Iki baslica diyabet tipi vardir; Tip 1 ve Tip 2: Tip 1 diyabet, pankreasin insülin üreten hücrelerinin (beta hücreleri) hasar görmesi nedeniyle olusur. Tip 1 diyabette pankreas çok az insülin yapar veya hiç insülin yapmaz, bu nedenle seker enerji olarak kullanilmak üzere vücudun hücrelerine giremez. Tip 1 diyabetli kisiler kan glikozunu kontrol etmek için insülin enjeksiyonlari kullanmalidir. Tip 2 diyabette pankreas insülin yapar ancak ya yeterince üretmez ya da insülin görevini düzgün sekilde yerine getirmez. Bu diyabet en sik 40 yas üstü ve asiri kilolu kisilerde görülür. Tip 2 diyabet bazen bir diyet, kilo yönetimi ve egzersiz kombinasyonu ile kontrol altina alinabilir. Bununla birlikte, tedavi ayrica oral glikoz düsürücü ilaçlari veya insülin enjeksiyonlarini da içerebilir. Metformin, oral yoldan uygulanan bir biguanid yapisina sahip antidiyabetiktir. Metformin hidroklorür beyaz ila kirli beyaz kristalin bir bilesiktir ve suda serbestçe çözünür ve aseton, eter ve kloroformda pratik olarak çözünmez. Metforminin oral dozlari genellikle günde 500 ila 2500 mg araliginda tavsiye edilir ve tek bir doz 500 ila 850 mg arasinda degisebilir. Tek basina veya sülfonilüreler, alfa- glukozidaz inhibitörleri veya insülin ile kombinasyon halinde kullanilir. Metformin hidroklorürün kimyasal adi 1,1-dimetilbiguanid hidroklorürdür, asagidaki Formül I'in kimyasal yapisina sahiptir. Formül I Empagliflozin, tip 2 diyabetli hastalarda glisemik kontrolde tedavi veya iyilestirme için tarif edilen bilinen bir SGLT2 inhibitörüdür. Empagliflozinin kimyasal adi 1-kloro-4-(3-D-glukopiranos-1 -il)- 2-[4- ((S)-tetrahidrofuran-3-iloksi)-benzil]-benzen olup kimyasal yapisi Formül II'de gösterilmistir. Formül II Empagliflozin ve metformin hidroklorürün kombinasyon ürünü Synjardy® ticari markasi altinda pazarlanmaktadir. Kombinasyonun, T2D'li kisilerde kan glikozunu kontrol etmeye yardimci olmasi beklenmektedir. Bir sodyum glikoz ko-tasiyici-2 (SGLTZ) inhibitörü olan empagliflozin, böbrekte glikoz yeniden emilimini bloke ederek fazla glikozu idrar yoluyla uzaklastirir. Etkin bilesenlerin formülasyon ve proseste bazi dezavantajlari vardir. Empagliflozin içeren formülasyonlar hazirlanirken karsilasilan temel problem, dagilma ve çözünme sürelerinde zorluklara yol açan düsük çözünürlüktür. Ayrica bilindigi gibi metformin çok zayif sikistirilabilir bir etkin maddedir ve metformin bir kompozisyonda yüksek miktarlarda bulunur. Bu, örnegin, homojenlik, akiskanlik ve çözünme profili gibi bir takim problemlere neden olur. W basvurusu, bir SGLT-2 inhibitör ilacinin ve bir ortak ilacin sabit doz kombinasyonlarini içeren farmasötik kompozisyonlari, bunlarin hazirlanmasina yönelik prosesleri ve bunlarin belirli hastaliklari tedavi etmek için kullanimlarini açiklar. CN basvurusu, empagliflozin ve metforminin farmasötik bir kompozisyonunu, bir hazirlama yöntemini ve bunun uygulamasini açiklar. Kompozisyon asagidaki bilesenleri içerir: i.) empagliflozin; ii.) metformin hidroklorür; ve bir veya daha fazla dolgu maddesi; bir veya daha fazla yapistirici; bir veya daha fazla akis yardimcisi ve bir veya daha fazla lubrikant. Önceki teknikte, oral farmasötik dozaj formlarinda empagliflozin ve metformin hidroklorürü açiklayan birkaç patent de bulunmaktadir. Bununla birlikte, etkili bir formülasyon ve yöntem henüz açiklanmamistir. Teknikte yüksek çözünürlüge, mükemmel farmakomekanik özelliklere ve buna bagli olarak yüksek bir biyoyararlanima ve yine etkili bir proses kullanilarak elde edilen uzun vadeli bir stabiliteye sahip olan empagliflozin ve metformin hidroklorür içeren, gelismis bir film kapli tablet formülasyonu saglanmasina hala bir ihtiyaç vardir. Bulusun Ayrintili Açiklamasi Mevcut bulusun ana amaci, sikistirilabilirlik, akiskanlik, homojenlik ve içerik tekdüzeligi gibi mükemmel fizikokimyasal özelliklere sahip olan, önceki teknige ait yukarida açiklanan problemlerin üstesinden gelen ve onlara göre ilave avantajlari bulunan, empagliflozin ve metformin hidroklorür içeren film kapli bir tablet saglamaktir. Mevcut bulusun diger bir amaci, istenen düzeyde çözünme hizina ve yüksek stabiliteye sahip olan, empagliflozin ve metformin hidroklorür içeren film kapli bir tablet saglamaktir. Mevcut bulusun diger bir amaci, empagliflozin ve metformin hidroklorür içeren film kapli bir tabletin hazirlanmasina yönelik bir proses saglamaktir. Proses, basit, hizli, maliyet etkin, zaman kazandiran ve endüstriyel olarak uygun bir yöntemdir. Burada kullanildigi sekliyle "intragranüler kompozisyon" terimi, solvent ile islatilan ve daha sonra kurutulan ve granüle edilen bir granül popülasyonunu ifade eder. Intragranüler kompozisyon ayni zamanda i'granül" veya i'granül bilesen" olarak da adlandirilabilir. "Ekstragranüler kompozisyon", yas granülasyona girmeyen kismi ifade eder. Empagliflozin içeren formülasyonlar hazirlanirken karsilasilan temel problem, dagilma ve çözünme sürelerinde zorluklara yol açan düsük çözünürlüktür. Ayrica, metformin çok zayif sikistirilabilir ve zayif akiskanliga sahip bir etkin maddedir ve metformin bir kompozisyonda yüksek miktarlarda bulunur. Bu, örnegin, sikistirilabilirlik, homojenlik, akiskanlik ve çözünme profili gibi bir takim problemlere neden olur. Bu nedenle, kullanilan eksipiyanlar ve proses adimlari çok önemlidir. Fizikokimyasal özellikler, tablet formülasyonunda önemli parametrelerdir. Bu özellikle yüksek miktarda etkin madde içeren formülasyonlarda bir problem olabilmektedir. Bir formülasyonda, bunlarla ilgili fizikokimyasal özelliklerdeki bir problem, çözünme profilini ve stabiliteyi olumsuz etkiler. Bu formülasyonda hem metformin HCI'nin yüksek miktarda olmasi hem de metforminin halihazirda akiskanlik ve sikistirilabilirlik problemlerinin bulunmasi nedeniyle yas granülasyon çok önemlidir. Bu bulusta, alkol içeren bir solvent ile yas granülasyonun bu problemlerin üstesinden geldigini bulduk. Mevcut bulusun bir düzenlemesine göre, film kapli bir tablet, empagliflozin ve metformin hidroklorür, en az bir baglayici içeren bir intragranüler kompozisyon içermekte olup, burada intragranüler kompozisyon alkol içeren bir solvent kullanilarak yas granülasyon yoluyla elde edilir. Baglayici kullaniminin sasirtici bir sekilde içerik tekdüzeligini, etkin maddenin istenen akiskanligini ve homojenligini sagladigini gördük. Formülasyonlar gelistirilirken karsilasilan problem, metformin HCI'nin üretimi zorlastiran sikistirilabilirligidir. Kullanilan proses ise bu problemin üstesinden gelmeyi Uygun baglayicilar, hidroksipropil selüloz, hidroksipropil metilselüloz, önceden jelatinize edilmis nisasta, karboksimetilselüloz sodyum, selüloz asetat ftalat, kitosan, dekstroz, etilselüloz, gliseril behenat, hidroksietil selüloz, hidroksietilmetil selüloz, hidroksipropil nisasta, magnezyum alüminyum silikat, poloksamer, polikarbofil, polidekstroz, polietilen oksit, polimetakrilatlar, polioksietilen-alkil eterler veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre baglayici, hidroksipropil metil selüloz veya hidroksipropil selülozdur. Tercihen baglayici, hidroksipropil selülozdur. Mevcut bulusun bir düzenlemesine göre, baglayicilarin miktari toplam kompozisyonda agirlikça %2.0 ila %15.0'tir. Tercihen, baglayicilarin miktari, toplam kompozisyonda agirlikça %2.0 ila %10.0'dur. Mevcut bulusun bir düzenlemesine göre, metformin hidroklorür miktari toplam kompozisyonda agirlikça %70.0 ila %90.0'dir. Tercihen, metformin hidroklorür miktari toplam kompozisyonda Mevcut bulusun bir düzenlemesine göre, empagliflozin miktari toplam kompozisyonda agirlikça %0.1 ila %5.0'tir. Tercihen, empagliflozin miktari toplam kompozisyonda agirlikça %03 ila %2.5'tir. Mevcut bulusun bir düzenlemesine göre, alkol içeren bir solvent, etil alkol-su karisimi veya metanol- su karisimi veya izopropil alkol-su karisimidir. Mevcut bulusun bir düzenlemesine göre, bir intragranüler kompozisyon ayrica en az bir dolgu maddesi içerir. Uygun dolgu maddeleri, misir nisastasi, mikrokristalin selüloz, laktoz, susuz laktoz, nisasta, manitol, kalsiyum hidrojen fosfat dihidrat, dikalsiyum hidrojen fosfat anhidrat, kalsiyum fosfat trihidrat, nötr peletler, magnezyum karbonat, magnezyum oksit, maltodekstrin, maltoz, orta zincirli trigliseritler veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre, dolgu maddesi, misir nisastasidir. Dolgu maddesi, toz karisiminin akiskanligini ve sikistirilabilirligini saglamaya yardimci olur. Mevcut bulusun bir düzenlemesine göre, dolgu maddesi miktari toplam kompozisyonda agirlikça Bu bulusun bir düzenlemesine göre, tablet ayrica en az bir lubrikant ve en az bir glidant içeren ekstragranüler bir kompozisyon içerir. Uygun glidantlar, susuz kolloidal silikon dioksit, sodyum stearil fumarat, magnezyum oksit, silikon dioksit, talk, polietilen glikol, alüminyum silikat, magnezyum silikat veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre, glidant, susuz kolloidal silikon dioksittir. Glidant, tabletin istenen akiskanligini ve sikistirilabilirligini saglamaya yardimci olur. Mevcut bulusun bir düzenlemesine göre glidantlarin miktari toplam kompozisyonda agirlikça %0.1 ila Uygun lubrikantlar, magnezyum stearat, kalsiyum stearat, potasyum stearat, stearik asit, sodyum klorür, sodyum benzoat, sodyum asetat, sodyum oleat, polietilen glikoller veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre, lubrikant, magnezyum stearattir. Mevcut bulusun bir düzenlemesine göre, lubrikant miktari toplam kompozisyonda agirlikça %0.1 ila Mevcut bulusun bir düzenlemesine göre, film kapli tablet, en az bir film kaplama maddesi ile kaplanir. Uygun film kaplama maddeleri, polimetakrilatlar, hidroksipropil metil selüloz, laktoz monohidrat, talk, hidroksipropil selüloz, polivinil alkol (PVA), polietilen glikol (PEG), gliserin, polivinil alkol- polietilen glikol kopolimerleri (Kollicoat® IR), etilselüloz dispersiyonlari (Surelease®), polivinilpirolidon, polivinilpirolidon-vinil asetat kopolimeri (PVP-VA), demir oksit sari, demir oksitler, tüm Opadry® türleri, pigmentler, boyalar, titanyum dioksit, boyar maddeler veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre, film kapli tablet sunlari içerir; a) Agirlikça %70.0 ila %90.0 Metformin HCI b) Agirlikça %0.1 ila %5.0 Empagliflozin c) Agirlikça %2.0 ila %15.0 baglayici d) Agirlikça %1.0 ila %12.0 dolgu maddesi e) Agirlikça %0.1 ila %8.0 glidant f) Agirlikça %0.1 ila %5.0 lubrikant. Mevcut bulusun bir düzenlemesine göre, film kapli tablet sunlari içerir; Metformin HCI Empagliflozin Misir nisastasi Hidroksipropil Selüloz Susuz kolloidal silikon dioksit Magnezyum stearat ve film kapli tablet, alkol içeren bir solvent ile yas granülasyon yoluyla elde edilir. Mevcut bulusun bir düzenlemesine göre, film kapli tablet hazirlanmasina yönelik bir proses, asagidaki adimlari içerir: Yas granüllerin kurutulmasi, Karisimin tabletler halinde basilmasi, Metformin HCl, empagliflozin, misir nisastasi ve hidroksipropil selülozun karistirilmasi, Karisimin alkol içeren bir solvent ile granüle edilmesi, Susuz kolloidal silikon dioksit ve magnezyum stearat ilave edilerek karistirilmasi, Tabletlerin film kaplama maddesi ile kaplanmasi. Bu mevcut bulusta, film kapli tabletin istenen bir akiskanligi, sikistirilabilirligi ve istenen bir içerik tekdüzeligi elde edilmekte olup, bu endüstriyel üretim lehine basit ve düsük maliyetli bir hazirlama prosesine sahiptir. Örnek 1: Tablet formülasyonu Bilesenler Agirlikça % Metformin HCI 80.0-90.0 Empagliflozin 0.3 - 2.5 Misir nisastasi 2.0-8.0 Hidroksipropil Selüloz 2.0 - 10.0 Susuz kolloidal silikon dioksit 0.1 - 8.0 Magnezyum stearat 0.1 - 5.0 TOPLAM 100 Örnek 1 için bir proses; a) Metformin HCl'nin 2 mm elekten geçirilmesi, b) Metformin HCl, empagliflozin, misir nisastasi ve hidroksipropil selüloz veya hidroksipropil metilselülozun karistirilmasi, c) Karisimin alkol içeren bir solvent ile granüle edilmesi, d) Yas granülün 8 mm elekten geçirilmesi, e) Yas granüllerin 50 °C'de kurutulmasi ve 1.5 mm elekten geçirilmesi, f) Susuz kolloidal silikon dioksit ve magnezyum stearat ilave edilerek karistirilmasi, g) Karisimin tabletler halinde basilmasi, h) Tabletlerin film kaplama maddesi ile kaplanmasi. TR TR TR TR TR TRDESCRIPTION A FORMULATION OF EMPAGLIFLOSIN AND METFORMIN HYDROCHLORIDE Field of the Invention The present invention relates to a film-coated tablet comprising an intragranular composition comprising empagliflozin and metformin hydrochloride and at least one binder, wherein the intragranular composition is obtained by wet granulation using an alcohol-containing solvent. The process is simple, rapid, cost-effective, time-saving and industrially feasible. Background of the Invention Diabetes mellitus is a group of disorders of carbohydrate metabolism in which insulin action is reduced or absent due to impaired secretion, decreased insulin activity, or a combination of both factors. There are two main types of diabetes; Type 1 and Type 2: Type 1 diabetes occurs due to damage to the insulin-producing cells (beta cells) of the pancreas. In type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot enter the body's cells to be used as energy. People with type 1 diabetes must use insulin injections to control blood glucose. In type 2 diabetes, the pancreas makes insulin but either does not produce enough or the insulin does not work properly. This type of diabetes is most common in people over age 40 and who are overweight. Type 2 diabetes can sometimes be controlled with a combination of diet, weight management, and exercise. However, treatment may also include oral glucose-lowering medications or insulin injections. Metformin is an orally administered biguanide antidiabetic. Metformin hydrochloride is a white to off-white crystalline compound that is freely soluble in water and practically insoluble in acetone, ether, and chloroform. Oral doses of metformin are generally recommended to range from 500 to 2500 mg per day, and a single dose can range from 500 to 850 mg. It is used alone or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin. The chemical name for metformin hydrochloride is 1,1-dimethylbiguanide hydrochloride and has the chemical structure of Formula I. Formula I Empagliflozin is a known SGLT2 inhibitor prescribed for the treatment or improvement of glycemic control in patients with type 2 diabetes. The chemical name for empagliflozin is 1-chloro-4-(3-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and its chemical structure is shown in Formula II. Formula II The combination product of empagliflozin and metformin hydrochloride is marketed under the trade name Synjardy®. The combination is expected to help control blood glucose in people with T2D. Empagliflozin, a sodium glucose cotransporter-2 (SGLTZ) inhibitor, blocks glucose reabsorption in the kidney and removes excess glucose via the urine. The active ingredients have some disadvantages in formulation and processing. The main problem encountered when preparing formulations containing empagliflozin is low solubility, which leads to difficulties in dispersion and dissolution times. It is also known that metformin is a very poorly compressible active ingredient and metformin is present in high amounts in a composition. This causes a number of problems, such as homogeneity, fluidity and dissolution profile. Application W discloses pharmaceutical compositions comprising fixed dose combinations of an SGLT-2 inhibitor drug and a co-drug, processes for their preparation, and their use to treat certain diseases. Application CN discloses a pharmaceutical composition of empagliflozin and metformin, a method of preparation, and its administration. The composition includes the following components: i.) empagliflozin; ii.) metformin hydrochloride; and one or more fillers; one or more adhesives; one or more flow aids; and one or more lubricants. Several patents also exist in the prior art that disclose empagliflozin and metformin hydrochloride in oral pharmaceutical dosage forms. However, an effective formulation and method have not yet been disclosed. There is still a need in the art to provide an improved film-coated tablet formulation containing empagliflozin and metformin hydrochloride having high solubility, excellent pharmacomechanical properties and hence high bioavailability and long-term stability achieved using an effective process. Detailed Description of the Invention The main object of the present invention is to provide a film-coated tablet containing empagliflozin and metformin hydrochloride having excellent physicochemical properties such as compressibility, flowability, homogeneity and content uniformity, overcoming the above-mentioned problems of the prior art and having additional advantages over them. Another object of the present invention is to provide a film-coated tablet containing empagliflozin and metformin hydrochloride having a desired dissolution rate and high stability. Another object of the present invention is to provide a process for the preparation of a film-coated tablet containing empagliflozin and metformin hydrochloride. The process is simple, rapid, cost-effective, time-saving and industrially suitable. The term "intragranular composition" as used herein refers to a population of granules that are wetted with solvent and then dried and granulated. The intragranular composition may also be referred to as "granule" or "granule component". The "extragranular composition" refers to the portion that does not undergo wet granulation. The main problem encountered when preparing formulations containing empagliflozin is low solubility, which leads to difficulties in disintegration and dissolution times. Furthermore, metformin is a very poorly compressible and poorly fluid active ingredient, and metformin is present in high amounts in a composition. This causes a number of problems, such as, for example, compressibility, homogeneity, flowability and dissolution profile. Therefore, the excipients used and the process steps are very important. Physicochemical properties are important parameters in tablet formulation. This can be a problem especially in formulations containing high amounts of active ingredients. A problem in the physicochemical properties related to these in a formulation negatively affects the dissolution profile and stability. In this formulation, wet granulation is very important both because of the high amount of metformin HCl and because metformin already has flowability and compressibility problems. In the present invention, we have found that wet granulation with an alcohol-containing solvent overcomes these problems. According to one embodiment of the present invention, a film-coated tablet comprises an intragranular composition comprising empagliflozin and metformin hydrochloride, at least one binder, wherein the intragranular composition is obtained by wet granulation using an alcohol-containing solvent. We have found that the use of binders provides surprisingly uniformity of content, desired fluidity and homogeneity of the active substance. A problem encountered in developing formulations is the compressibility of metformin HCI, which makes its production difficult. The process used overcomes this problem. Suitable binders are selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch, carboxymethylcellulose sodium, cellulose acetate phthalate, chitosan, dextrose, ethylcellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl starch, magnesium aluminum silicate, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, polyoxyethylene-alkyl ethers or mixtures thereof. According to an embodiment of the present invention, the binder is hydroxypropyl methyl cellulose or hydroxypropyl cellulose. Preferably, the binder is hydroxypropyl cellulose. According to an embodiment of the present invention, the amount of binders is 2.0 to 15.0 wt% of the total composition. Preferably, the amount of binders is 2.0 to 10.0 wt% of the total composition. According to an embodiment of the present invention, the amount of metformin hydrochloride is 70.0 to 90.0 wt% of the total composition. Preferably, the amount of metformin hydrochloride is in the total composition. According to an embodiment of the present invention, the amount of empagliflozin is 0.1 to 5.0 wt% of the total composition. Preferably, the amount of empagliflozin is 0.3 to 2.5 wt% of the total composition. According to one embodiment of the present invention, an alcohol-containing solvent is an ethyl alcohol-water mixture or a methanol-water mixture or an isopropyl alcohol-water mixture. According to one embodiment of the present invention, an intragranular composition further comprises at least one filler. Suitable fillers are selected from the group consisting of corn starch, microcrystalline cellulose, lactose, anhydrous lactose, starch, mannitol, calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate anhydrate, calcium phosphate trihydrate, neutral pellets, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides or mixtures thereof. According to one embodiment of the present invention, the filler is corn starch. The filler helps to provide flowability and compactibility of the powder mixture. According to one embodiment of the present invention, the amount of filler is by weight in the total composition. According to one embodiment of the present invention, the tablet further comprises an extragranular composition comprising at least one lubricant and at least one glidant. Suitable glidants are selected from the group consisting of anhydrous colloidal silicon dioxide, sodium stearyl fumarate, magnesium oxide, silicon dioxide, talc, polyethylene glycol, aluminum silicate, magnesium silicate, or mixtures thereof. According to one embodiment of the present invention, the glidant is anhydrous colloidal silicon dioxide. The glidant helps provide the desired flowability and compressibility of the tablet. According to one embodiment of the present invention, the amount of glidants is between 0.1% by weight of the total composition. Suitable lubricants are selected from the group consisting of magnesium stearate, calcium stearate, potassium stearate, stearic acid, sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols or mixtures thereof. According to one embodiment of the present invention, the lubricant is magnesium stearate. According to one embodiment of the present invention, the amount of lubricant is between 0.1% by weight of the total composition. According to one embodiment of the present invention, the film-coated tablet is coated with at least one film-coating agent. Suitable film coating materials are selected from the group consisting of polymethacrylates, hydroxypropyl methyl cellulose, lactose monohydrate, talc, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), glycerin, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), iron oxide yellow, iron oxides, all Opadry® types, pigments, dyes, titanium dioxide, dyestuffs or mixtures thereof. According to one embodiment of the present invention, the film-coated tablet comprises; a) 70.0 to 90.0 wt% Metformin HCl b) 0.1 to 5.0 wt% Empagliflozin c) 2.0 to 15.0 wt% binder d) 1.0 to 12.0 wt% filler e) 0.1 to 8.0 wt% glidant f) 0.1 to 5.0 wt% lubricant. According to one embodiment of the present invention, the film-coated tablet contains; Metformin HCl Empagliflozin Corn starch Hydroxypropyl Cellulose Anhydrous colloidal silicon dioxide Magnesium stearate and the film-coated tablet is obtained by wet granulation with a solvent containing alcohol. According to one embodiment of the present invention, a process for preparing film-coated tablets comprises the following steps: Drying the wet granules, Compressing the mixture into tablets, Mixing metformin HCl, empagliflozin, corn starch and hydroxypropyl cellulose, Granulating the mixture with an alcohol-containing solvent, Adding anhydrous colloidal silicon dioxide and magnesium stearate and mixing, Coating the tablets with the film-coating agent. In the present invention, a desired fluidity, compressibility and a desired content uniformity of the film-coated tablet are obtained, which has a simple and low-cost preparation process in favor of industrial production. Example 1: Tablet formulation Ingredients % by weight Metformin HCl 80.0-90.0 Empagliflozin 0.3 - 2.5 Corn starch 2.0-8.0 Hydroxypropyl cellulose 2.0 - 10.0 Anhydrous colloidal silicon dioxide 0.1 - 8.0 Magnesium stearate 0.1 - 5.0 TOTAL 100 A process for Example 1; a) Passing metformin HCl through a 2 mm sieve, b) Mixing metformin HCl, empagliflozin, corn starch and hydroxypropyl cellulose or hydroxypropyl methylcellulose, c) Granulating the mixture with a solvent containing alcohol, d) Passing the wet granules through an 8 mm sieve, e) Drying the wet granules at 50 °C and passing them through a 1.5 mm sieve, f) Adding anhydrous colloidal silicon dioxide and magnesium stearate and mixing, g) Compressing the mixture into tablets, h) Coating the tablets with a film-coating agent. TR TR TR TR TR TR

Claims

STEMS

It is a film-coated tablet containing an intragranular composition containing empagliflozin and metformin hydrochloride and at least one binder, the feature of which is that the intragranular composition is obtained by wet granulation using an alcohol-containing solvent.

It is a film-coated tablet according to claim 1, and its feature is that the binders are hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch, polyvinylpyrrolidone, carboxymethylcellulose sodium, cellulose acetate phthalate, chitosan, dextrose, ethylcellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethylcellulose. sulose, hydroxypropyl starch , magnesium aluminum silicate, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, polyoxyethylene-alkyl ethers or mixtures thereof.

It is a film-coated tablet according to claim 1, and its feature is that the binder is hydroxypropyl methyl cellulose or hydroxypropyl cellulose.

Film-coated tablet according to claim 1, characterized in that the amount of binders is 2.0 to 15.0% by weight in the total composition.

It is a film-coated tablet according to claim 1, and its feature is that the alcohol-containing solvent is ethyl alcohol-water mixture or methanol-water mixture or isopropyl alcohol-water mixture.

Film-coated tablet according to claim 1, characterized in that an intragranular composition also contains at least one filler.

It is a film-coated tablet according to claim 6, and its feature is that it contains fillers, corn starch, microcrystalline cellulose, lactose, anhydrous lactose, starch, mannitol, calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate anhydrate, calcium phosphate trihydrate, neutral pellets, magnesium carbonate, magnesium. oxide, maltodextrin, maltose, medium chain triglycerides or mixtures thereof.

It is a film-coated tablet according to claim 7, and its feature is that the filler is corn starch.

Film-coated tablet according to claim 8, characterized in that the amount of filler is 1.0 to 12.0% by weight in the total composition.

It is a film-coated tablet according to claim 6, further characterized in that it contains an extragranular composition containing at least one lubricant and at least one glidant.

11. Film-coated tablet according to claim 10, characterized in that the glidants are selected from the group consisting of anhydrous colloidal silicon dioxide, sodium stearyl fumarate, magnesium oxide, silicon dioxide, talc, polyethylene glycol, aluminum silicate, magnesium silicate or mixtures thereof. It is a film-coated tablet according to claim 10, characterized in that the lubricants are selected from the group consisting of magnesium stearate, calcium stearate, potassium stearate, stearic acid, sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols or mixtures thereof. It is a film-coated tablet according to claim 10, and its feature is that the film-coated tablet contains the following; 70.0% to 90.0% by weight Metformin HCl 0.1% to 5.0% by weight Empagliflozin 2.0% to 15.0% by weight binder 1.0% to % by weight

12.0 filler 0.1 to 8.0% by weight glidant 0.1 to 5.0% by weight lubricant. It is a film-coated tablet according to claim 10, and its feature is that the film-coated tablet contains the following; Metformin HCl Empagliflozin Corn starch Hydroxypropyl Cellulose Anhydrous colloidal silicon dioxide Magnesium stearate and film-coated tablet are obtained by wet granulation with an alcohol-containing solvent. It is a process for the preparation of a film-coated tablet and includes the following steps: Mixing metformin HCl, empagliflozin, corn starch and hydroxypropyl cellulose, Granulating the mixture with an alcohol-containing solvent, Drying the wet granules, Adding anhydrous colloidal silicon dioxide and magnesium stearate and mixing. Pressing the mixture into tablets, coating the tablets with a film coating agent.