TR2023016461A1

TR2023016461A1 - A COMBINATION OF GLIPTIN AND ROSUVASTATIN

Info

Publication number: TR2023016461A1
Application number: TR2023/016461
Authority: TR
Inventors: Ra Ari Bu; Z Tunc Gulden; Gultek N Nce Ozlem; Pehl Van Akalin Nur
Original assignee: Sanovel İlaç Sanayi̇ Ve Ti̇caret Anoni̇m Şi̇rketi̇
Filing date: 2023-12-05
Publication date: 2025-06-23

Abstract

Mevcut buluş, bir gliptin ve rosuvastatin içeren bir farmasötik kombinasyona ilişkindir. Bu tür bir kombinasyonun hazırlanmasına yönelik yöntemler de sağlanmaktadır. Açıklama, ayrıca bu tür formülasyonların Tip 2 diyabetli hastalarda diyet ve egzersize yardımcı olarak glisemik kontrolün iyileştirilmesi ve/veya yönetimi için kullanılmasıyla da ilgilidir.The present invention relates to a pharmaceutical combination comprising a gliptin and rosuvastatin. Methods for preparing such a combination are also provided. The disclosure also relates to the use of such formulations for improving and/or managing glycemic control as an adjunct to diet and exercise in patients with Type 2 diabetes.

Description

TARIFNAME BIR GLIPTIN VE ROSUVASTATIN IÇEREN BIR KOMBINASYON Bulusun alani Mevcut bulus, bir gliptin ve rosuvastatin içeren bir farmasötik kombinasyona iliskindir. Bu tür bir kombinasyonun hazirlanmasina yönelik yöntemler de saglanmaktadir. Açiklama, ayrica bu tür formülasyonlarin Tip 2 diyabetli hastalarda diyet ve egzersize yardimci olarak glisemik kontrolün iyilestirilmesi ve/veya yönetimi için kullanilmasiyla da ilgilidir. Bulusun geçmisi Rosuvastatin kalsiyum, HMG-CoA redüktaz inhibitörünün seçici ve rekabetçi bir inhibitörü olan sentetik bir lipit düsürücü maddedir. Kimyasal adi bis[(E)-7-[4-(4-florofenil)-6-izopropil-2- kimyasal yapisi Formül I'de gösterilmektedir. Sûziile Formül I Rosuvastatin kalsiyum, CRESTOR® markasi altinda pazarlanmaktadir ve hiperlipoproteinemi, hiperkolesterolemi ve aterosklerozun tedavisi için yaklasik 5 mg'dan yaklasik 40 mg'a kadar günlük bir dozda uygulanmaktadir. Daha önce bir veya daha fazla oral anti-diyabetik madde ve/veya bir veya daha fazla enjekte edilebilir anti-diyabetik madde (örn. insülin) ile tedavi edilmis olan bir memeli hastada tip 2 diyabetin tedavisi için bilinmektedir. Bazen bunlar yetersiz görülmektedir. Rosuvastatin yaygin olarak diger antidiyabetik ilaçlarla birlikte bir kombinasyon tedavisinde kullanilir. Mevcut bulusta, terapötik etkiyi arttirmak, olumsuz etkileri hafifletmek ve hasta uyumunu gelistirmek için farkli etki mekanizmalarina sahip iki veya daha fazla antidiyabetik maddenin bir kombinasyonu saglanmaktadir. Bu tür çabalarin sonucunda, bir gliptin (teneligliptin veya gemigliptin) ve rosuvastatinin kombinasyonuyla bu tür amaçlara ulasilabilecegini bulduk ve böylece mevcut bulusu tamamladik. Gliptinler, glukagon benzeri peptid-1'in (GLP-l) inaktivasyonunu katalize eden ve DPP-IV inhibitörleri olarak bilinen enzimlerdir. DPP-4 inhibitörleri, inkretin hormonunu yikan bir enzim olan DPP-4'ün etkisini bloke ederek çalisir. Vücutta glukagon benzeri peptid-1(GLP-1)ve glikoza bagimli insülinotropik peptid (GIP) adi verilen iki tip inkretin hormonu bulunur. Bu hormonlar gida alimina yanit olarak vücut tarafindan dogal olarak üretilir. Islevleri, vücudun yalnizca ihtiyaç duyuldugunda daha fazla insülin üretmesine yardimci olmak ve ihtiyaç duyulmadiginda karaciger tarafindan üretilen glikoz miktarini azaltmaktir. Sitagliptin, DPP-4'e baglanarak ve onun GLP-l ve GIP'i parçalamasini engelleyerek çalisir. Bu, vücuttaki bu hormonlarin seviyelerini arttirir ve böylece kan sekerinin kontrolü üzerindeki etkilerini Su anda sitagliptin, vildagliptin, saksagliptin, teneligliptin, gemigliptin, alogliptin ve linagliptin gibi gliptinler, geleneksel tablet dozaj formlari halinde mevcuttur. Teneligliptin, hipoglisemik aktiviteye sahip, uzun etkili, oral olarak biyoyararlanabilen, pirrolidin bazli bir dipeptidil peptidaz 4 (DPP-4) inhibitörüdür. Teneligliptin ayrica GLP-l düzeylerinde sürekli bir artis yoluyla plazma trigliserit düzeylerini de azaltabilir. Teneligliptin, Tip 2 Diyabetin tedavisi için arastirilmistir. Gemigliptin inkretin'i aktive ederek kan sekeri seviyesinde stabil bir düsüs gösterir. Ayrica gemigliptin, geleneksel oral antidiyabetiklerin hipoglisemi ve kilo alimi gibi kusurlarina sahip degildir ve düsük kardiyovasküler bozukluk riski gösterir, böylece halihazirda sülfonilüreleri geride birakmistir. Bu nedenle, glisemik kontrol açisindan, hastalik modifiye edici özellikler açisindan ve kardiyovasküler morbidite ve mortalitenin azaltilmasi açisindan iyi bir etkililige sahip olup, ayni zamanda gelismis bir güvenlik profili gösteren yöntemlere, ilaçlara ve farmasötik kombinasyonlara hâlâ bir ihtiyaç bulunmaktadir. Bu bulusta ikiden fazla molekülün bir dozaj formunda kombine edilmesi hastanin uyumunu artirmaktadir. Kombinasyon, ilgili önceki teknige ilave avantajlar kazandirmaktadir. Öte yandan, mevcut bulusa göre kombine edilecek olan her ilacin daha düsük bir dozunun kullanilmasi, toplam dozaji azaltacaktir. Bunlar tedavi edilecek hastalar açisindan avantajlidir. Bulusun ayrintili açiklamasi Mevcut bulusun ana amaci, bir memelide tip 2 diyabetin ve/veya kalp hastaliginin tedavisinde kullanim için sinerjistik etkiye sahip, bir gliptin ve rosuvastatin içeren stabil bir kombinasyon elde etmektir. Mevcut bulusun bir diger amaci gliptin ve rosuvastatin içeren bir formülasyon saglamaktir. Mevcut bulusun bir diger amaci, istenen çözünme profiline, homojenlige, yüksek stabiliteye ve akiskanliga sahip, bir gliptin ve rosuvastatin içeren bir formülasyon saglamaktir. Bu bulus ayni zamanda tip 2 diyabet tedavisinden muzdarip bir insanin tedavisinde kullanilmak üzere bir miktar gliptin, özellikle gemigliptin veya teneligliptin ve bir miktar rosuvastatin içeren bir farmasötik kombinasyon saglamakta olup, burada bir gliptin ve rosuvastatin ayni anda, ayri ayri ve sirali olarak uygulanir. Burada kullanildigi sekliyle "rosuvastatin" terimi, serbest baz formunda veya farmasötik açidan kabul edilebilir tuzlar, kristalin polimorf, solvatlar, hidratlar, esterler veya bunlarin karisimlari formundaki fingolimodu ifade eder. Burada kullanildigi sekliyle "teneligliptin" terimi, serbest baz formunda veya farmasötik açidan kabul edilebilir tuzlar, kristalin polimorf, solvatlar, hidratlar, esterler veya bunlarin karisimlari formundaki gabapentini ifade eder. Burada kullanildigi sekliyle "gemigliptin" terimi, serbest baz formundaki veya farmasötik açidan kabul edilebilir tuzlar, kristalin polimorf, solvatlar, hidratlar, esterler veya bunlarin karisimlari formundaki pregabalini ifade eder. Bu bulusta formülasyonda kullanilan etkin bilesenlerin yüzdesi düsüktür. Etkin bilesenlerin formülasyonda homojenlik ve akiskanlik problemi olmadan bulunmasi ve istenen çözünme profilini vermesi çok önemlidir. Etkin madde oranina bakilmaksizin formülasyonda belirtilen dagitici oranlarinda kullanildiginda homojenligin ve akiskanligin çok iyi oldugunu tespit ettik. Bu, böylece istenen çözünme profilini saglar. Ayrica belirli oranlarda dagitici kullanmanin stabiliteyi saglamaya yardimci oldugunu da bulduk. Mevcut bulusun bir baska düzenlemesine göre, bir gliptin ve rosuvastatin kalsiyum ve en az bir dagitici içeren bir farmasötik kombinasyon olup, burada dagiticilarin miktari, toplam formülasyon içerisinde agirlikça %0.5 ile %10.0 arasindadir. Mevcut bulusun baska bir düzenlemesine göre, etkin maddelerin (gliptin ve rosuvastatin) dagiticiya agirlik orani 1.0-20.0'dir, tercihen etkin maddelerin (gliptin ve rosuvastatin) dagiticiya agirlik orani 1.0- .0'dir, daha tercihen etkin maddelerin (gliptin ve rosuvastatin) dagiticiya agirlik orani 1.0-10.0'dir. Mevcut bulusun bir baska düzenlemesine göre gliptin miktari, toplam formülasyon içerisinde agirlikça tercihen toplam formülasyonda agirlikça %0.2 ile %9.5 arasindadir. Mevcut bulusun bir baska düzenlemesine göre rosuvastatin kalsiyumun miktari, toplam formülasyonda arasindadir. Daha tercihen toplam formülasyonda agirlikça %03 ile %8.0 arasindadir. Mevcut bulusun bir baska düzenlemesine göre bir gliptin, sitagliptin, vildagliptin, saksagliptin, teneligliptin, gemigliptin, alogliptin veya linagliptin içeren gruptan seçilir. Mevcut bulusun bir baska düzenlemesine göre tercihen bir gliptin, teneligliptin veya gemigliptindir. Mevcut bulusun bir baska düzenlemesine göre teneligliptin miktari, toplam formülasyon içerisinde agirlikça %0.1 ile %7.5 arasindadir. Mevcut bulusun bir baska düzenlemesine göre gemigliptin miktari, toplam formülasyon içerisinde agirlikça %4.0 ile %10.0 arasindadir. Uygun dagiticilar, krospovidon, povidon, kroskarmeloz sodyum, önceden jelatinize edilmis nisasta, sodyum karboksimetil selüloz, kalsiyum karboksimetil selüloz, karboksimetil selüloz, dokusat sodyum, düsük ikameli hidroksipropil selüloz, sodyum aljinat, misir nisastasi, sodyum nisasta glikolat, aljinik asit, aljinatlar, magnezyum alüminyum silika, sodyum dodesil sülfat, poloksamer, sodyum glisin karbonat, sodyum lauril sülfat veya bunlarin karisimlarini içeren gruptan seçilir. Mevcut bulusun bir baska düzenlemesine göre dagitici krospovidondur. Mevcut bulusun bir baska düzenlemesine göre dagitici miktari, toplam formülasyonda agirlikça %0.7 ile %7.0 arasindadir. Mevcut bulusa göre tercih edilen bir düzenlemede adi geçen kombinasyon ayrica dolgu maddeleri, baglayicilar, lubrikantlar, glidantlar, kaplama maddeleri veya bunlarin karisimlari arasindan seçilen farmasötik açidan kabul edilebilir en az bir eksipiyan içerir. Uygun dolgu maddeleri, mikrokristalin selüloz, mannitol, dikalsiyum fosfat anhidrat, spreyle kurutulmus mannitol, laktoz, laktoz monohidrat, susuz laktoz, nisasta, dekstroz, sakaroz, fruktoz, maltoz, sorbitol, ksilitol, kaolin, inorganik tuzlar, kalsiyum tuzlari, polisakkaritler, dikalsiyum fosfat, sodyum klorür, sakaroz-maltodekstrin karisimi, trehaloz, sodyum karbonat, sodyum bikarbonat, kalsiyum karbonat veya bunlarin karisimlarini içeren gruptan seçilir. Mevcut bulusun bir baska düzenlemesine göre dolgu maddesi, mikrokristalin selüloz veya dikalsiyum fosfat anhidrat veya susuz laktoz veya mannitol veya nisasta veya bunlarin karisimlaridir. Mevcut bulusun bir baska düzenlemesine göre dolgu maddelerinin miktari, toplam formülasyon içerisinde agirlikça %60.0 ile %93.0 arasindadir. Tercihen toplam formülasyonda agirlikça %78.0 ile Uygun baglayicilar, hidroksipropil selüloz, polivinilpirolidon, polietilen glikol, polivinil alkol, önceden jelatinize edilmis nisasta, glikoz, glikoz surubu, dogal sakizlar, sakaroz, sodyum aljinat, hidroksipropil metil selüloz, karboksi metil selüloz, metil selüloz, jelatin, karragenan, guar zamki, karbomer, polimetakrilatlar, metakrilat polimerleri, aljinat, aljinik asit, ksantan zamki, hyaluronik asit, polisakaritler, karbomer, poloksamer, poliakrilamid, polidekstroz, polietilen oksit veya bunlarin karisimlarini içeren gruptan seçilir. Mevcut bulusun bir baska düzenlemesine göre baglayici, hidroksipropil selülozdur. Mevcut bulusun bir baska düzenlemesine göre baglayicilarin miktari, toplam formülasyonda agirlikça Uygun lubrikantlar, magnezyum stearat, kalsiyum stearat, çinko stearat, vakslar, borik asit, hidrojene bitkisel yag, sodyum klorat, magnezyum lauril sülfat, sodyum oleat, sodyum asetat, sodyum benzoat, polietilen glikol, stearik asit, yag asidi, fumarik asit, sodyum stearil fumarat, sodyum lauril sülfat veya bunlarin karisimlarini içeren gruptan seçilir. Mevcut bulusun bir baska düzenlemesine göre, lubrikant magnezyum stearattir. Uygun glidantlar, kolloidal silikon dioksit, misir nisastasi, talk veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir baska düzenlemesine göre glidant, kolloidal silikon dioksittir. Uygun kaplama maddeleri, polimetakrilatlar, polialkilakrilatlar kopolimerleri, hidroksil propil metil selüloz, laktoz monohidrat, hidroksipropil selüloz, polivinil alkol, polietilen glikol, talk, polivinil alkol- polietilen glikol kopolimerleri (Kollicoat® IR), etilselüloz dispersiyonlari (Surelease®), polivinilprolidon, polivinilprolidon-vinil asetat kopolimeri (PVP-VA), her türlü Opadry®, pigmentler, boyalar, titanyum dioksit, demir oksit veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre farmasötik kombinasyon oral yoldan uygulanir. Farmasötik kombinasyon, tablet, kapsül, serit, surup, toz, pastil, sase, efervesan kompozisyon, hap, kaplanmis boncuk sistemi, granül, mikroküre, film, agizdan uygulanabilen film, solüsyon, kati, süspansiyon veya emülsiyon formundadir. Tercihen farmasötik kombinasyon tablet veya kapsül formundadir. Mevcut bulusun bir baska uygulamasina göre farmasötik kombinasyon, tablet formundadir. Farmasötik kombinasyon film kapli tablet, iki katmanli tablet, iç içe tablet (inlay tablets), agizda dagilan tablet, sikistirilmis tablet, kaplanmis veya kaplanmamis tablet, çok katmanli tablet, mini tablet, bukkal tablet, dil alti tablet, efervesan tablet, midede dagilan tablet, çignenebilen tablet, dispersiyon tablet veya lozenge içeren tabletler olarak formüle edilir. Tercihen farmasötik kombinasyon, film kapli tablet veya iki katmanli tablet formundadir. Mevcut bulusun bir baska düzenlemesine göre farmasötik kombinasyon, iki katmanli tablet formundadir. Mevcut bulusun bir baska düzenlemesine göre farmasötik kombinasyon, bir kapsül formundadir. Kombinasyon, direk baski, yas veya kuru granülasyon, sicak eriyik granülasyon, sicak eriyik ekstrüzyon, akiskan yatakli granülasyon, ekstrüzyon, sferonizasyon, briket tablet basma (slugging), spreyle kurutma veya solvent evaporasyon yöntemi kullanilarak hazirlanir. Mevcut bulusun bir baska düzenlemesine göre, kombinasyon yas veya kuru granülasyon yöntemiyle Bu mevcut bulusta, kombinasyonun istenen bir çözünmesi elde edilmekte ve istenen bir içerik tekdüzeligi ve basit bir hazirlama prosesi endüstriyel üretim lehine olmaktadir. Örnek 1: Bir gemigliptin ve rosuvastatin içeren kombinasyon Bilesenler Agirlikça % Agirlikça % Agirlikça % anhidrat iri beyaz toz Toplam 100 100 100 Örnek 1 için bir proses; a) Gemigliptin ile kolloidal silikon dioksitin karistirilmasi, b) Krospovidon CL ve mikrokristalin selülozun ilave edilip karistirilmasi, c) Rosuvastatin kalsiyum ile dikalsiyum fosfat anhidratin karistirilmasi, d) Adim (b)'deki karisimin ve adim (c)'deki karisimin ve susuz laktozun 630 u elenmesi ve karistirilmasi, e) Karisimin 630 u elenmesi, f) Magnezyum stearatin ilave edilmesi ve karistirilmasi, g) Karisimin tablet olusturmak üzere basilmasi, h) Tabletlerin film kaplama ile kaplanmasi. Örnek 2: Teneligliptin ve rosuvastatin içeren kombinasyon Bilesenler Agirlikça % Agirlikça % Agirlikça % m 15.38 g beyaz toz Toplam 100 100 100 Film kaplama 0.1-4.0 3.1 3.1 Örnek 2 için bir proses; 1-Birinci katman a) Teneligliptin, mannitol ve nisastanin karistirilmasi, b) HPC'nin saf suda çözülmesi ve granülasyon çözeltisi elde edilmesi ve çözeltinin adim (a)'daki karisima eklenmesi, c) Karisimin akiskan yatakli kurutucuda nem orani %2 olana kadar kurutulmasi, d) Krospovidon CL ve magnezyum stearat ilave edilip karistirilmasi, 2-Ikinci katman e) Rosuvastatin kalsiyum ile dikalsiyum fosfat anhidratin karistirilmasi, f) Mikrokristalin selüloz ilave edilerek karistirilmasi, g) Susuz Laktozun ilave edilip karistirilmasi, h) Krospovidon CL ve magnezyum stearat ilave edilip karistirilmasi, 3-Birinci katman ile ikinci katmanin sikistirilarak iki katmanli tablet olusturulmasi, 4-Iki katmanli tabletlerin film kaplamayla kaplanmasi. TR TRDESCRIPTION A COMBINATION COMPRISING A GLIPTIN AND ROSUVASTATIN Field of the invention The present invention relates to a pharmaceutical combination comprising a gliptin and rosuvastatin. Methods for preparing such a combination are also provided. The disclosure also relates to the use of such formulations for the improvement and/or management of glycemic control as an adjunct to diet and exercise in patients with Type 2 diabetes. Background of the invention Rosuvastatin calcium is a synthetic lipid-lowering agent that is a selective and competitive inhibitor of HMG-CoA reductase inhibitor. Its chemical name is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-] and its chemical structure is shown in Formula I. Supplemental Formula I Rosuvastatin calcium is marketed under the brand name CRESTOR® and is administered in a daily dose of approximately 5 mg to approximately 40 mg for the treatment of hyperlipoproteinemia, hypercholesterolemia, and atherosclerosis. It is known for the treatment of type 2 diabetes in mammalian patients who have been previously treated with one or more oral antidiabetic agents and/or one or more injectable antidiabetic agents (e.g., insulin). These are sometimes found to be inadequate. Rosuvastatin is commonly used in combination therapy with other antidiabetic medications. The present invention provides a combination of two or more antidiabetic agents with different mechanisms of action to enhance the therapeutic effect, mitigate adverse effects, and improve patient compliance. Through such efforts, we have found that such goals can be achieved with a combination of gliptin (teneligliptin or gemigliptin) and rosuvastatin, thus completing the current invention. Gliptins are enzymes known as DPP-IV inhibitors that catalyze the inactivation of glucagon-like peptide-1 (GLP-1). DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme that breaks down the incretin hormone. The body contains two types of incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). These hormones are naturally produced by the body in response to food intake. Their function is to help the body produce more insulin only when needed and to reduce the amount of glucose produced by the liver when not needed. Sitagliptin works by binding to DPP-4 and preventing it from breaking down GLP-1 and GIP. This increases the levels of these hormones in the body and thereby influences blood sugar control. Gliptins such as sitagliptin, vildagliptin, saxagliptin, teneligliptin, gemigliptin, alogliptin, and linagliptin are currently available in conventional tablet dosage forms. Teneligliptin is a long-acting, orally bioavailable pyrrolidine-based dipeptidyl peptidase 4 (DPP-4) inhibitor with hypoglycemic activity. Teneligliptin may also reduce plasma triglyceride levels through a sustained increase in GLP-1 levels. Teneligliptin is being investigated for the treatment of type 2 diabetes. Gemigliptin activates incretin, producing a stable lowering of blood sugar levels. Furthermore, gemigliptin does not have the drawbacks of traditional oral antidiabetic agents, such as hypoglycemia and weight gain, and exhibits a low risk of cardiovascular disorders, thus already surpassing sulfonylureas. Therefore, there remains a need for methods, drugs, and pharmaceutical combinations that demonstrate good efficacy in glycemic control, disease-modifying properties, and reduction of cardiovascular morbidity and mortality, while also demonstrating an improved safety profile. In this invention, combining more than two molecules in a single dosage form improves patient compliance. The combination offers additional advantages over the relevant prior art. Furthermore, using a lower dose of each drug combined according to the present invention will reduce the total dosage, which is advantageous for the patients being treated. Detailed description of the invention The main object of the present invention is to provide a stable combination comprising a gliptin and rosuvastatin having a synergistic effect for use in the treatment of type 2 diabetes and/or heart disease in a mammal. Another object of the present invention is to provide a formulation comprising gliptin and rosuvastatin. Another object of the present invention is to provide a formulation comprising a gliptin and rosuvastatin having a desired dissolution profile, homogeneity, high stability and flowability. The present invention also provides a pharmaceutical combination comprising an amount of gliptin, in particular gemigliptin or teneligliptin, and an amount of rosuvastatin for use in the treatment of a human suffering from type 2 diabetes, wherein a gliptin and rosuvastatin are administered simultaneously, separately and sequentially. The term "rosuvastatin" as used herein refers to fingolimod in the free base form or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixtures thereof. The term "teneligliptin" as used herein refers to gabapentin in the free base form or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixtures thereof. The term "gemigliptin" as used herein refers to pregabalin in the free base form or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or mixtures thereof. The percentage of active ingredients used in the formulation in this invention is low. It is crucial that the active ingredients are present in the formulation without any homogeneity or fluidity issues and that they achieve the desired dissolution profile. We have found that homogeneity and fluidity are very good when the specified dispersant ratios are used in the formulation, regardless of the active ingredient ratio. This, in turn, provides the desired dissolution profile. We have also found that using specific dispersants helps ensure stability. According to another embodiment of the present invention, a pharmaceutical combination comprising a gliptin and rosuvastatin calcium and at least one dispersant is provided, wherein the amount of dispersants is between 0.5% and 10.0% by weight of the total formulation. According to another embodiment of the present invention, the weight ratio of the active substances (gliptin and rosuvastatin) to the disintegrant is 1.0-20.0, preferably the weight ratio of the active substances (gliptin and rosuvastatin) to the disintegrant is 1.0-0.0, more preferably the weight ratio of the active substances (gliptin and rosuvastatin) to the disintegrant is 1.0-10.0. According to another embodiment of the present invention, the amount of gliptin is preferably between 0.2 and 9.5% by weight in the total formulation. According to another embodiment of the present invention, the amount of rosuvastatin calcium is between 0.3 and 8.0% by weight in the total formulation. More preferably, it is between 0.3 and 8.0% by weight in the total formulation. According to another embodiment of the present invention, a gliptin is selected from the group consisting of sitagliptin, vildagliptin, saxagliptin, teneligliptin, gemigliptin, alogliptin or linagliptin. According to another embodiment of the present invention, preferably a gliptin is teneligliptin or gemigliptin. According to another embodiment of the present invention, the amount of teneligliptin is between 0.1 and 7.5% by weight in the total formulation. According to another embodiment of the present invention, the amount of gemigliptin is between 4.0 and 10.0% by weight in the total formulation. Suitable disintegrants are selected from the group consisting of crospovidone, povidone, croscarmellose sodium, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, low substituted hydroxypropyl cellulose, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, magnesium aluminum silica, sodium dodecyl sulfate, poloxamer, sodium glycine carbonate, sodium lauryl sulfate or mixtures thereof. According to another embodiment of the present invention, the disintegrant is crospovidone. According to another embodiment of the present invention, the amount of disintegrant is between 0.7 and 7.0% by weight of the total formulation. In a preferred embodiment according to the present invention, said combination further comprises at least one pharmaceutically acceptable excipient selected from fillers, binders, lubricants, glidants, coating agents or mixtures thereof. Suitable fillers are selected from the group comprising microcrystalline cellulose, mannitol, dicalcium phosphate anhydrate, spray-dried mannitol, lactose, lactose monohydrate, anhydrous lactose, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof. According to another embodiment of the present invention, the filler is microcrystalline cellulose or dicalcium phosphate anhydrate or anhydrous lactose or mannitol or starch or mixtures thereof. According to another embodiment of the present invention, the amount of fillers is between 60.0% and 93.0% by weight in the total formulation. Preferably 78.0% by weight of the total formulation. Suitable binders are selected from the group comprising hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, hydroxypropyl methyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, alginate, alginic acid, xanthan gum, hyaluronic acid, polysaccharides, carbomer, poloxamer, polyacrylamide, polydextrose, polyethylene oxide or mixtures thereof. According to another embodiment of the present invention, the binder is hydroxypropyl cellulose. According to another embodiment of the present invention, the amount of binders is by weight in the total formulation. Suitable lubricants are selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, sodium stearyl fumarate, sodium lauryl sulfate, or mixtures thereof. According to another embodiment of the present invention, the lubricant is magnesium stearate. Suitable glidants are selected from the group consisting of colloidal silicon dioxide, corn starch, talc, or mixtures thereof. According to another embodiment of the present invention, the glidant is colloidal silicon dioxide. Suitable coating materials are selected from the group consisting of polymethacrylates, polyalkylacrylates copolymers, hydroxyl propyl methyl cellulose, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), all types of Opadry®, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof. According to one embodiment of the present invention, the pharmaceutical combination is administered orally. The pharmaceutical combination is in the form of a tablet, capsule, strip, syrup, powder, lozenge, sachet, effervescent composition, pill, coated bead system, granule, microsphere, film, orally administerable film, solution, solid, suspension or emulsion. Preferably, the pharmaceutical combination is in the form of a tablet or capsule. According to another embodiment of the present invention, the pharmaceutical combination is in the form of a tablet. The pharmaceutical combination is formulated as film-coated tablets, bilayer tablets, inlay tablets, orally disintegrating tablets, compressed tablets, coated or uncoated tablets, multilayer tablets, minitablets, buccal tablets, sublingual tablets, effervescent tablets, gastric disintegrating tablets, chewable tablets, dispersion tablets or tablets comprising lozenges. Preferably, the pharmaceutical combination is in the form of a film-coated tablet or bilayer tablet. According to another embodiment of the present invention, the pharmaceutical combination is in the form of a bilayer tablet. According to another embodiment of the present invention, the pharmaceutical combination is in the form of a capsule. The combination is prepared by direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, spheronization, briquette tablet compression (slugging), spray drying or solvent evaporation. According to another embodiment of the present invention, the combination is prepared by wet or dry granulation. In the present invention, a desired dissolution of the combination is achieved and a desired content uniformity and a simple preparation process favor industrial production. Example 1: A combination comprising gemigliptin and rosuvastatin Ingredients Wt % Wt % Wt % anhydrate coarse white powder Total 100 100 100 A process for Example 1; a) Mixing gemigliptin with colloidal silicon dioxide, b) Adding crospovidone CL and microcrystalline cellulose and mixing, c) Mixing rosuvastatin calcium with dicalcium phosphate anhydrate, d) Sifting and mixing the mixture in step (b) and the mixture in step (c) and anhydrous lactose 630, e) Sifting the mixture 630, f) Adding magnesium stearate and mixing, g) Compressing the mixture to form tablets, h) Covering the tablets with film coating. Example 2: Combination containing teneligliptin and rosuvastatin Components % by weight % by weight m 15.38 g white powder Total 100 100 100 Film coating 0.1-4.0 3.1 3.1 A process for Example 2; 1-First layer a) Mixing teneligliptin, mannitol, and starch, b) Dissolving HPC in pure water to obtain a granulation solution and adding the solution to the mixture in step (a), c) Drying the mixture in a fluidized bed dryer until the moisture content is 2%, d) Adding crospovidone CL and magnesium stearate and mixing, 2-Second layer e) Mixing rosuvastatin calcium and dicalcium phosphate anhydrate, f) Adding microcrystalline cellulose and mixing, g) Adding anhydrous lactose and mixing, h) Adding crospovidone CL and magnesium stearate and mixing, 3-Compressing the first and second layers to form a bilayer tablet, 4-Coating the bilayer tablets with a film coat. TR TR

Claims

REQUESTS

It is a pharmaceutical combination comprising a gliptin and rosuvastatin calcium and at least one disintegrant, characterized in that the amount of disintegrants is between 0.5% and 10.0% by weight in the total formulation.

Pharmaceutical combination according to claim 1, characterized in that the amount of gliptin is between 0.1% and 15.0% by weight in the total formulation.

The pharmaceutical combination according to claim 1, characterized in that the amount of rosuvastatin calcium is between 0.1 and 15.0% by weight in the total formulation.

Pharmaceutical combination according to claim 1, characterized in that a gliptin is selected from the group comprising sitagliptin, vildagliptin, saxagliptin, teneligliptin, gemigliptin, alogliptin or linagliptin.

Pharmaceutical combination according to claim 1 or 4, characterized in that a gliptin is teneligliptin or gemigliptin.

Pharmaceutical combination according to claim 5, characterized in that the amount of teneligliptin is between 0.1% and 75% by weight in the total formulation.

Pharmaceutical combination according to claim 6, characterized in that the amount of gemigliptin is between 4.0% and 10.0% by weight in the total formulation.

Pharmaceutical combination according to claim 1, characterized in that the disintegrants are selected from the group comprising crospovidone, povidone, croscarmellose sodium, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, low substituted hydroxypropyl cellulose, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, magnesium aluminum silica, sodium dodecyl sulfate, poloxamer, sodium glycine carbonate, sodium lauryl sulfate or mixtures thereof.

Pharmaceutical combination according to claim 1 or 9, characterized in that the disintegrant is crospovidone.

10) Pharmaceutical combination according to claim 1, characterized in that it further comprises at least one pharmaceutically acceptable excipient selected from fillers, binders, lubricants, glidants, coating agents or mixtures thereof.

11) Pharmaceutical combination according to claim 12, characterized in that the fillers are selected from the group comprising microcrystalline cellulose, mannitol, dicalcium phosphate anhydrate, spray-dried mannitol, lactose, lactose monohydrate, anhydrous lactose, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.

12) Pharmaceutical combination according to claim 12, characterized in that the filler is microcrystalline cellulose or dicalcium phosphate anhydrate or anhydrous lactose or mannitol or starch or mixtures thereof.

13) Pharmaceutical combination according to claim 12, characterized in that the binders are selected from the group comprising hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, glucose, glucose syrup, natural gums, sucrose, sodium alginate, hydroxypropyl methyl cellulose, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, alginate, alginic acid, xanthan gum, hyaluronic acid, polysaccharides, carbomer, poloxamer, polyacrylamide, polydextrose, polyethylene oxide or mixtures thereof.

14) Pharmaceutical combination according to claim 12, characterized in that the binder is hydroxypropyl cellulose.

15) Pharmaceutical combination according to claim 1, characterized in that the pharmaceutical combination is in tablet or capsule form.