TR2022007224T2 - PHARMACEUTICAL COMPOSITION CONTAINING TENOFOVIR AND EMTRICITABINE - Google Patents
PHARMACEUTICAL COMPOSITION CONTAINING TENOFOVIR AND EMTRICITABINEInfo
- Publication number
- TR2022007224T2 TR2022007224T2 TR2022/007224 TR2022007224T2 TR 2022007224 T2 TR2022007224 T2 TR 2022007224T2 TR 2022/007224 TR2022/007224 TR 2022/007224 TR 2022007224 T2 TR2022007224 T2 TR 2022007224T2
- Authority
- TR
- Turkey
- Prior art keywords
- emtricitabine
- tenofovir disoproxil
- film
- tenofovir
- tablet
- Prior art date
Links
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 title abstract description 81
- 229960000366 emtricitabine Drugs 0.000 title abstract description 65
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 24
- 229960004556 tenofovir Drugs 0.000 title abstract description 16
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 title 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 abstract description 52
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 abstract description 52
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 abstract description 30
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 abstract description 27
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Abstract
Mevcut buluş; Tenofovir ve Emtrisitabin içeren stabil bir farmasötik bileşimin hazırlanması, ek olarak ilgili eksipiyanların kullanımı, bunun yanısıra kuru granülasyon yöntemi kullanılarak geliştirilmiş bir üretim prosesi ve depolama stabilitesi ile ilgilidir. Tenofovir Disoproksil Fumarat ve Emtrisitabin iki ayrı kuru granül olarak hazırlanır. Toplam tablet bileşimi içerisinde Karboksimetil Selüloz Sodyum ve Magnezyum Stearatın oranı 1,2:1-2,0:1 (a/a) aralığındadırThe present invention; The preparation of a stable pharmaceutical composition comprising Tenofovir and Emtricitabine further relates to the use of relevant excipients, as well as an improved production process and storage stability using the dry granulation method. Tenofovir Disoproxil Fumarate and Emtricitabine are prepared as two separate dry granules. The ratio of Carboxymethyl Cellulose Sodium and Magnesium Stearate in the total tablet composition is in the range of 1.2:1-2.0:1 (w/w).
Description
TARIFNAME TENOFOVIR VE EMTRISITABIN IÇEREN FARMASÖTIK BILESIM Bulusun Ilgili Oldugu Teknik Alan Bu bulus, tenofovir ve emtrisitabin içeren farmasötik bilesimin hazirlanmasi ile ilgilidir. Bulus ayrica, ilgili eksipiyanlar ile birlikte, kuru granülasyon yöntemi kullanilarak gelistirilmis bir üretim prosesi ve depolama stabilitesi ile ilgilidir. Bulusun Arka Plani Insan Bagisiklik Yetmezligi Virüsü (HIV) enfeksiyonu ve buna bagli hastaliklar dünya üzerindeki baslica halk sagligi problemlerinden biridir. Tenofovir ve emtrisitabin, HIV enfeksiyonu tedavisi için kullanilirlar. Bilesiklerin kombinasyonunun kullanilmasi, azalan toksisite ile birlikte esdeger bir antiviral etki veya ilaç etkinliginde artis ortaya çikarir. Tenofovir bir nükleotid ters transkriptaz inhibitörüdür (NRTI). HIV enfeksiyonundaki ters transkriptaz aktivitesini engeller, HIV tarafindan üretilen bu enzim hücrelerin enfekte olmasina ve virüslerin çogalmasina yol açar. Tenofovir disoproksil fumarat, tenofovirin fumarik asit tuzu formunda bir ön ilaç olup adenozinin nükleozid ters transkriptaz inhibitör analogudur. Tenofovir disoproksil fumarat, tenofovir disoproxil ve fumarik asitin esdeger miktarlari ile hazirlanan bir fumarat tuzudur. Bu ilacin baska ilaçlar ile kombinasyonunun, Hepatit B terapisinde oldugu gibi, HIV enfeksiyonu tedavisinde de kullanildigi reçetelenmistir. Tenofovir disoproksil fumaratin kimyasal ismi [[(2R)-l-(6-aminopürin-9-il)propan-2- il]oksimetil-(propan-2-iloksikarboniloksimetoksi)fosforil]oksimetil propan-2-il karbonat; (E)- büt-2-enedioik asit,tir ve kimyasal yapisi asagida gösterilmistir. k/ûvl-°^OÂUJ\ *i ;02" .EHB (1`,on HÇI-ßlc _RH Tenofovir Disoproksil Fumarat Emtrisitabin, yetiskinlerde HIV enfeksiyonu tedavisinde kullanilan bir nükleozid ters transkriptaz inhibitörüdür (NRTI). Emtrisitabin, bir sitidin analogudur. Emtrisitabinin kimyasal sinifi Nükleozid Analogdur. Ilaç, HIV ters transkriptazi inhibe ederek, HIV,in RNA,dan DNAaya transkripsiyonunu önleyerek çalisir. Emtrisitabinin kimyasal ismi, 4-amino-5-Iloro-l-[(2R,5S)-2-(hidroksimetil)-l ,3-oksatiyolan- -il]pirimidin-2-on,dur ve kimyasal yapisi asagida gösterilmistir. attigi" M ;CH Emtrisitabin Tenofovir Disoproksil Fumarat / Emtrisitabin, pazarda film-kapli tablet bilesiminde bulunur. 245 mg/ 200 mg,lik terapötik dozda oral olarak uygulanir ve ve yetiskinlerin HIV enfeksiyon tedavisinde kullanilir. Tenofovir Disoproksil Fumarat/Emtrisitabin GILEAD tarafindan 245/200 mg dozaj formlarinda Truvada® ticari markasi ile pazara sunulmustur. Insan vücudunda HIV virüsünün çogalmasina karsi bagisiklik yetersizligini önlemek için kullanilir. HIV virüsünün sebep olabilecegi Edinsel Bagisiklik Eksikligi Sendromu (AIDS) hastaligini tedavi etmek için kullanilir. Truvada®; kroskarmeloz sodium, laktoz monohidrat, magnezyum stearat, mikrokristal selüloz ve prejelatinize nisasta (glutensiz) içermektedir. Emtrisitabin ve Tenofovir Disproksil Fumaratain hizli salinim tableti farkli dagiticilar kullanilarak formülize edilmis ve degerlendirilmistir. Bu çalismanin esas amaci; Emtrisitabin ve Tenofovir Disproksil Fumarat içeren hizli salinim tabletinin farkli dagiticilar kullanilarak formülize edilmesi ve degerlendirilmesidir. Bu çalisma; (Manikandan M., Kannan K.*, Selvamuthukumar S. and Manavalan R., Composition development and evaluation of Emtricitabine and Tenofovir Disproxil Fumarate Tablets, International Journal of Drug Development & Research. January-March 2012 | Vol. 4 | Issue 1) isimli bilimsel makaleye dayanarak gerçeklestirilmistir. EP1890681 A2 Emtrisitabin/Tenofovir DFaye ait bir farmasötik bilesim ile ilgili olup bu bilesim farmasötik olarak uygun bir eksipiyan, Tenofovir DF ve Emtrisitabin bilesenlerinin kuru granülasyonu ile elde edilir. EP3326619 Al Tenofovir/Emtrisitabin aktif maddelerini ve nisastasiz eksipiyan içeren, HIV-l ve hepatit B tedavisinde kullanilan bir farmasötik bilesim ile ilgilidir. Tablet kompozisyonu yas granülasyon ile hazirlanir. WO20 l 5 085 976Al yas granülasyon ile tablet hazirlamaya yönelik stabil bir farmasötik bilesim ile ilgili olup bu bilesim Tenofovir Disoproksil Fumarat veya Tenofovir Disoproksil Fumaratin baska bir aktif madde ve bir dagitici madde ile kombinasyonunu içerir. Kroskarmeloz sodyum yerine; krospovidon, misir nisastasi ve hidroksipropil selüloz grubu içinden bir dagitici seçilmesi, Tenofovir Disoproksil Fumaratin Tenofovir Disoproksil Hemifumarata dönüsümünü veya Emtrisitabinin farmasötik olarak uygun bir tuzu ve Efavirenz veya Efavirenzin farmasötik olarak uygun bir tuzunun kombinasyonu ile ilgilidir. Proses yas granülasyon ile gerçeklestirilir. Bulus Özeti Mevcut bulus, HIV enfeksiyonu tedavisinde kullanilmak üzere Tenofovir Disoproksil Fumarat ve Emtrisitabin içeren farmasötik bir bilesimin hazirlanmasi ile ilgilidir. Mevcut bulus, HIV enfeksiyonu tedavisinde kullanilmak üzere hazirlanan Tenofovir Disoproksil Fumarat ve Emtrisitabin içeren farmasötik bilesim ile ilgili olup bu kompozisyonun kuru granülasyon yöntemi ile üretimini içermektedir. Mevcut bulus, Tenofovir Disoproksil Fumarat, Emtrisitabin, Kroskarmeloz Sodyum ve Magnezyum Stearat içeren farmasötik bir bilesim ile ilgili olup total tablet kompozisyonu içerisinde kroskarmeloz sodyum ve magnezyum stearatin kütlece birlesim oraninin 1,2: l-2,0:l (a/ a) araliginda olmasidir. Belirtilen bilesim için, kroskarmeloz sodyum ve magnezyum stearatin toplam tablet kompozisyonu içerisindeki kütlece birlesim orani l,2:l-2,0:l (a/a), öncelikle l,4:l-l,8:l (a/a), daha da öncelikle l,5:l-l,6:l (a/a) araliginda oldugunda; bilesimin dissolüsyon profili ve biyoyararlanimi üzerinde sinerj ik bir etkisi oldugu gözlenmistir. Bulusun Detayli Açiklamasi Mevcut bulus, Edinsel Bagisiklik Eksikligi Sendromuana (AIDS) sebep olabilecek virüsle ilgili HIV enfeksiyonunun tedavisinde kullanilmak üzere, Tenofovir Disoproksil Fumarat ve Emtrisitabin içeren farmasötik bir bilesimin hazirlanmasi ile ilgilidir. Yas granülasyonda kullanilan su ve kurutma prosesinde kullanilan isi faktörlerine bagli olarak, etken madde olan Tenofovir ve Emtrisitabin hidroliz yoluyla degrade olur. Yas granülasyonda organik solventlerin ( izopropil alkol, etanol) kullanimi, potansiyel çevresel risk faktörlerini ve proses maliyetini aitirmaktadir. Bu nedenle üretim yöntemi olarak kuru granülasyon tercih edilmektedir. Mevcut bulusun esas amaci, Tenofovir DF ve Emtrisitabin içeren stabil bir tablet bilesimini kuru granülasyon yöntemi ile elde etmektir. Bu proseste, aktif maddelerin degredasyonunun (hidrolizinin) esas sebebini olusturan su ve isi içeren yas granülasyon prosesi yerine, kuru granülasyon yöntemi kullanilmaktadir. Bu proseste kullanilan kuru granülasyon, yas granülasyona göre daha hizli gerçeklesmektedir. Bir diger amaç; Tenofovir Disoproksil Fumarat ve Emtrisitabin bilesiminde bir film kapli tablet kompozisyonunu hazirlamak için basit, uygun maliyetli ve zaman kazandiran gelistirilmis bir üretim prosesinin saglanmasidir. Bu proseste, kuru granülasyonun yas granülasyona göre çok sayida avantaji bulunmaktadir. Kuru granülasyon yönteminin kullanilmasindan dolayi, akis semasinda çok uygun maliyetli bir kompozisyon ortaya çikar. Mevcut bulus, istemlerde açiklandigi gibi teknigin bilinen durumunda tanimlanmis olan problemlerin üstesinden gelen ve bilinen duruma ek avantajlar saglayan Tenofovir Disoproksil Fumarat ve Emtrisitabinin yeni bir bilesimini ortaya koymaktadir. Bir diger amaç; Tenofovir Disoproksil Fumarat, Emtrisitabin ve eksipiyanlar içeren farmasötik bilesimin, biyoesdegerlige ve raf ömrü boyunca stabiliteye sahip olmasidir. Mevcut bulusun bir diger amaci; yüksek stabilite ve biyoyararlanima sahip Tenofovir DF ve Emtrisitabin kombinasyon bilesimlerini elde etmektir. Mevcut bulusun bir diger amaci, gelismis çözünürlük hizi ve dissolüsyona sahip Tenofovir DF ve Emtrisitabin kombinasyon kompozisyonlarini elde etmektir. Kroskarmeloz sodyum ve magnezyum stearatin kütlece birlesim orani toplam tablet kompozisyonunda l,2:l-2,0:l (a/a) araliginda oldugunda, dissolüsyon ve biyoesdegerlik çalisma sonuçlarinda sinerj ik etki gözlenmistir. Mevcut bulusun bir diger amaci, iki farkli asamaya sahip olmasidir: Kuru granül-l ve kuru granül-2. Tenofovir Disoproksil Fumarat, Kuru granül-l asamasinda eklenirken Emtrisitabin Kuru granül-2 asamasinda eklenir. Bu asamalar ayri ayri gerçeklestirildikten sonra, Kuru granül-l ve Kuru granül-2 birbiri ile karistirilir. Karistirma adimini takiben tablet baski, film kaplama ve ambalajlama adimlari gerçeklestirilir. Mevcut bulus; HIV enfeksiyon tedavisine yönelik olarak Tenofovir Disoproksil Fumarat, Emtrisitabin, Kroskarmeloz Sodyum ve Magnezyum Stearat içeren farmasötik bir bilesimini ortaya koymaktadir, burada kroskarmeloz sodyum ve magnezyum stearatin kütlece oranlari l,2:l-2,0:l (a/a) araliginda, öncelikle l,4:l-l,8:l (a/a) araliginda, daha öncelikle l,5:l-l,6:l (a/a) araligindadir. Mevcut bulus ek olarak, bir Tenofovir Disoproksil Fumarat ve Emtrisitabin içeren bir farmasötik bilesim; a) tenofovir disoproksil fumarat granülleri kuru granülasyon yöntemi ile kuru granül-l olarak hazirlanir, b) emtrisitabin granülleri kuru granülasyon yöntemi ile kuru granül-2 olarak hazirlanir, c) eksipiyan olarak kroskarmeloz sodyum ve magnezyum stearat içerir, burada kroskarmeloz sodyum ve magnezyum stearatin toplam tablet kompozisyonundaki orani l,2:l-2,0:l (a/a), öncelikle l,4:l-l,8:l (a/a), daha öncelikle l,5:l-l,6:l (a/a) araligindadir. Bir açidan kompozisyonda; dagiticilar, seyrelticiler, baglayicilar, lubrikantlar ve glidantlar içeren bir grup içinden seçilen farmasötik olarak uygun en az bir eksipiyan bulunabilir. Kompozisyon, dagitici ve/veya baglayici olarak Mikrokristal Selüloz ve Prejelatinize Nisasta içerebilir. Kompozisyon, seyreltici olarak Laktoz Monohidrat içerebilir. Kompozisyon, glidant olarak Kolloid Silikon Dioksit ve Talk içerebilir. Mevcut bulustaki kompozisyon, herhangi bir kati oral dozaj formunda olabilir. Mevcut bulusa bagli olarak tercih edilen dozaj formu tablettir, daha öncelikli olarak film kapli tablettir. Seyrelticiler, suda çözünür veya suda çözünmez olabilir. Seyrelticiler; sinirlandirilmamakla birlikte, spreyle kurutulmus (SD) veya anhidrus laktoz, laktoz monohidrat, sukroz, dekstroz, nisasta, prejelatinize nisasta, mannitol, maltitol, sorbitol, ksilitol, dekstrin, toz halinde selüloz içeren selüloz türevleri, mikrokristal selüloz, dibazik kalsiyum fosfat, tribazik kalsiyum fosfat ve kalsiyum sülfat, kaolin, çökeltilmis kalsiyum karbonat, maltodekstrin ve teknigin bilinen durumundaki diger benzer maddeleri içeren bir grup içerisinden seçilebilir. Tercih edilen seyrelticiler, laktoz (SD) ve/veya laktoz monohidrat ve/veya mikrokristal selülozdur. Seyrelticilerin bir karisimi da kullanilabilir. Baglayicilar; sinirlandirilmamakla birlikte, metilselüloz, sodyum karboksimetilselüloz, kalsiyum karboksimetil selüloz, etil selüloz, hidroksipropil metilselüloz, hidroksietilselüloz, hidroksipropil selüloz, silifiye mikrokristal selüloz, polivinil pirolidon, jelatin, polivinil alkol, Arap zamki, tragacanth, guar, pektin, nisasta kolasi, prejelatinize nisasta, alginik asit, sikistirilabilir seker, likit glukoz, dekstratlar, dekstrin, dekstroz, maltodekstrin, guar reçinesi, magnezyum alüminyum silikat, polimetakrilat, sorbitol, sükraloz ve teknigin bilinen durumundaki diger benzer maddeleri içeren bir grup içerisinden seçilebilir. Tercih edilen baglayici, prejelatinize nisastadir. Baglayicilarin karisimi da kullanilabilir. Dagiticilar; sinirlandirilmamakla birlikte, alginik asit, karboksimetil selüloz kalsiyum, karboksimetil selüloz, karboksimetil selüloz sodyum, çapraz bagli sodyum karboksimetil selüloz, düsük sübstitüyeli hidroksipropil selüloz, kolloidal silikon dioksit, kroskarmeloz sodyum, krospovidon, guar reçinesi, magnezyum alüminyum silikat, mikrokristal selüloz, metil selüloz, polivinil pirolidon, çapraz bagli polivinil pirolidonlar, polakrilin potasyum, nisasta, prejelatinize nisasta, sodyum alginat, sodyum lauril sülfat, sodyum nisasta glikolat, kristal selüloz, hidroksipropil nisasta ve teknigin bilinen durumundaki diger benzer maddeleri içeren bir grup içerisinden seçilebilir. Burada sözü edilen dagiticilarin kombinasyonu da kullanilabilir. Tercih edilen dagitici kroskarmeloz sodyum ve laktoz monohidrattir. Dagiticilarin karisimi da kullanilabilir. Lubrikantlar; sinirlandirilmamakla birlikte, hidrojenlenmis bitkisel yag veya hidrojenlenmis kastor yagi gibi bitkisel yaglar, polietilen glikol (PEG)-4000 ve PEG-6000 gibi polietilen glikoller, stearik asit, magnezyum stearat, sodyum stearat, kalsiyum stearat, çinko stearat, gliseril monostearat, gliseril palmitostearat ve sodyum stearil fumarat gibi stearik asit türevleri, talk gibi mineral tuzlar, inorganik tuzlar, sodyum benzoat, sodyum asetat, sodyum klorür ve sodyum oleat gibi organik tuzlar, ve poliVinil alkoller, mikrokristal selüloz, sodyum lauril sülfat, silika, kolloidal silika, misir nisastasi, kalsiyum silikat, magnezyum silikat, silikon hidrojel ve teknigin bilinen durumundaki diger benzer maddeleri içeren bir grup içerisinden seçilebilir. Tercih edilen lubrikant magnezyum stearattir. Lubrikantlarin karisimi da kullanilabilir. Glidantlar; sinirlandirilmamakla birlikte, kolloidal silikon dioksit, kolloidal silika, misir nisastasi, talk, kalsiyum silikat, magnezyum silikat, magnezyum trisilikat, amorf silika, kolloidal silikon, silikon hidroj el, toz halde selüloz, silikon dioksit, talk, tribazik kalsiyum fosfat ve teknigin bilinen durumundaki diger benzer maddeleri içeren bir grup içerisinden seçilebilir. Tercih edilen glidantlar, kolloidal silikon dioksit ve talktir. glidantlarin karisimi da kullanilabilir. Dolgu maddeleri; sinirlandirilmamakla birlikte, kalsiyum karbonat, kalsiyum fosfat, kalsiyum sülfat, karboksimetil selüloz kalsiyum, karboksimetil selüloz sodyum, sikistirilabilir seker, pudra sekeri, dekstratlar, dekstrin, dekstroz, dibazik kalsiyum fosfat dihidrat, dibazik kalsiyum fosfat, fruktoz, gliseril palmitostearat, glisin, hidrojenlenmis bitkisel yag-tip l, kaolin, laktoz, laktoz monohidrat, magnezyum karbonat, magnezyum oksit, maltodekstrin, mannitol, mikrokristal selüloz, polimetakrilat, potasyum klorür, toz halde selüloz, misir nisastasi, prejelatinize nisasta, sodyum klorür, sorbitol, nisasta, sukroz, seker küreleri, talk, tribazik kalsiyum fosfat, ksilitol ve teknigin bilinen durumundaki diger benzer maddeleri içeren bir grup içerisinden seçilebilir. Tercih edilen dolgu maddesi laktoz monohidrattir. Dolgu maddelerinin karisimi da kullanilabilir. Film kaplama ajani; sinirlandirilmamakla birlikte, hidroksipropil selüloz, hidroksimetil selüloz, etil selüloz, talk, polietilen glikol, titanyum dioksit, laktoz monohidrat, sari demir oksit, triasetin ve teknigin bilinen durumundaki diger benzer maddeleri içeren bir grup içerisinden seçilebilir. Film kaplama ajanlarinin karisimi da kullanilabilir. Tenofovir Disoproksil Fumarat granülü içeren Kuru granül-l, asagidaki asamalardan geçerek hazirlanabilir; a. Tenofovir Disoproksil Fumarat, Kroskarmeloz Sodyum, Mikrokristal Selüloz, Laktoz Monohidrat, Prejelatinize Nisasta, Talk ve Kolloidal Silikon Dioksidin elenmesi Bilesenlerin karistirilmasi Magnezyum Stearatin elenmesi, Bilesenlerin karistirilmasi Slugging Tüm eksipiyanlarin elenmesi Emtrisitabin granülü içeren Kuru granül-2, asagidaki asamalardan geçerek hazirlanabilir; a. Emtrisitabin, Kroskarmeloz Sodyum, Mikrokristal Selüloz, Prejelatinize Nisasta ve Kolloidal Silikon Dioksidin elenmesi c. Magnezyum Stearatin elenmesi e. Slugging Mevcut bulus, farmasötik bilesimin hazirlanmasi ile ilgili olarak asagidaki adimlardan olusan prosesi de kapsamaktadir; Kuru granül-l ve Kuru granül-2,nin karistirilmasi Magnezyum Stearatin elenmesi, Bilesenlerin karistirilmasi Tablet baski Karistirma Film kaplama Ambalajlama Mevcut bulus, Tenofovir Disoproksil Fumarat, Emtrisitabin ve ilgili eksipiyanlari içeren asagidaki gibi karakterize edilen farmasötik bilesimi kapsamaktadir; i) Uygun stabilite ii) Istenen terapötik etkilere sahip aktif maddenin saliniminin programlanmasi iii) Basit ve rekabetçilüretim prosesi. Bilesimdeki eksipiyanlarin fonksiyonu ve seçimi; bilesimdeki ilacin ayrismasi üzerinde mümkün olan en küçük etkiye sahip olabilecek eksipiyanlara duyulan gereksinime ve gerekli Bir açidan, Tenofovir Disoproksil Fumarat ve Emtrisitabin içeren tablet bilesiminin hazirlanma prosesi, asagidaki asamalari içerebilir; (Sekil 1) Kuru granül-l a. Eleme: Tenofovir Disoproksil Fumarat, Kroskarmeloz Sodyum, Mikrokristal Selüloz, Laktoz Monohidrat, Prejelatinize Nisasta, Talk ve Kolloidal Silikon Dioksit, b. Karistirma c. Magnezyum Stearati eleme d. a ve c asamalarindaki bilesenlerin karistirilmasi e. Slugging Kuru granül-2 g. Eleme: Emtrisitabin, Kroskarmeloz Sodyum, Mikrokristal Selüloz, Prejelatinize Nisasta ve Kolloidal Silikon Dioksit, h. g asamasindaki bilesenlerin karistirilmasi i. Magnezyum Stearatin elenmesi g ve i asamalarindaki bilesenlerin karistirilmasi k. Slugging . Kuru granül-1 ve Kuru granül-2,nin karistirilmasi Tablet basilmasi Film kaplamasi Ambalaj lama Mevcut bulusla ilgili kompozisyonlar HIV tedavisinde kullanilabilir. Mevcut bulus, HIV tedavisine yönelik olarak asagidaki gibi bir farmasötik bilesimi de kapsar; Tablo 1: Tenofovir DF / Emtrisitabin film kapli tabletin final kompozisyonu (245mg/200mg) Birim Formül Tenofovir Disoproksil Fumarat Etken Madde 300,00 29,85 Emtrisitabin Etken Madde 200,00 19,90 Kroskarmeloz Sodyum Dagitici 40,00 3,98 Mikrokristal Selüloz Baglayici, Dagitici N/A N/A Laktoz Monohidrat Seyreltici N/A N/A Prejelatinize Nisasta Baglayici, Dagitici N/A N/A Kolloidal Silikon Dioksit Lubrikant N/A N/A Talk Lubrikant N/A N/A Magnezyum Stearat Glidant 25,00 2,49 Çekirdek Tablet N/A N/A Opadry II Light Blue Y-30-10671-A Film Kaplama Malzemesi N/A N/A Distile su Çözücü N/A N/A Film Kapli Tablet N/A 100,00 Opadry II Light Blue Y-30-10671-A Içerik Miktar (%, a/a) Laktoz Monohidrat 40,00 Titanyum Dioksit 22,51 Triasetin 8,00 Fd&C Blue #2/Indigo Carmine Aluminum Lake (% 3-5) 1,49 Dissolüsyon ve Biyoesdegerlik Çalismalari Tenofovir Disoproksil Fumarat ve Emtrisitabin içeren farmasötik bilesim; Karboksimetil Selüloz Sodyum ve Magnezyum Stearatin 1,2:1-2,0:1 (a/a) araliginda olacak sekilde kullanilmistir. Dissolüsyon ve Pivotal Biyoesdegerlik çalisma sonuçlari; Karboksimetil Selüloz Sodyum ve Magnezyum Stearatin 1,2:1-2,0:1 (a/a) araliginda olacak sekilde kullanilmasi ile tatmin edici sonuçlar vermistir. Final Kompozisyon Için In-vitro Çalismalari Karboksimetil Selüloz Sodyum ve Magnezyum Stearat 1,2: 1-2,0:1 (a/a) araliginda olmak üzere, Tenofovir Disoproksil Fumarat ve Emtrisitabin içeren farmasötik bilesim için in-vitro çalisma sonuçlari asagida verilmektedir. Final tablet kompozisyonu Tablo 1,de gösterilmektedir. Tablo 2: Emtrisitabin / Tenofovir Disoproksil 200 mg/ 245 mg Film Tabletlerin Karsilastirmali Dissolüsyon Profilleri (0.01 N HCl ortami / pH 4.5 sodyum fosfat ortami / pH 6.8 fosfat tamponu ortami) (Tenofovir Disoproksil) 0.01 N HCl ortami pH 4.5 sodyum fosfat pH 6.8 fosfat tamponu ortami ortami Tenofovir Disoproksil Tenofovir Disoproksil Tenofovir Disoproksil Ortalama % Dissolüsyon Ortalama % Dissolüsyon Ortalama % Dissolüsyon Süre (Emtrisitabin / T enofovir (Emtrisitabin / T enofovir (Emtrisitabin / T enofovir mg Film Tablet) mg Film Tablet) mg Film Tablet) Mevcut bulusta sözü edilen farmasötik bilesim; "Emtrisitabin / Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet [Truvada 200 mg / 245 mg Film Tablet (Batch No: MMHND / Üretici firma: Gilead Sciences Intl Ltd.) ve Emtricitabin / Tenofovir Disoproxil 200 mg / 245 mg Film test edilmis olup, 900 mL,de ölçülen dissolüsyon hizi 50 rpm,dir. Örneklerdeki tenofovir / pH 4.5 sodyum fosfat ortami / pH 6.8 fosfat tamponu ortami için hesaplanmistir. (Sekil 2, 3, Tablo 3: Emtrisitabin / Tenofovir Disoproksil 200 mg/ 245 mg Film Tabletlerin Karsilastirmali Dissolüsyon Profilleri (0.01 N HCl ortami / pH 4.5 sodyum asetat ortami / pH 6.8 fosfat 0.01 N H Cl ortami pH 4.5 sodyum asetat pH 6.8 fosfat tamponu ortami ortami Emtrisitabin Ortalama Emtrisitabin Ortalama Emtrisitabin Ortalama % Time (Emtrisitabin / T enofovir (Emtrisitabin / T enofovir (Emtrisitabin / T enofovir mg Film Tablet) mg Film Tablet) Film Tablet) Mevcut bulusta sözü edilen farmasötik bilesim; "Emtrisitabin / Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet [Truvada 200 mg / 245 mg Film Tablet (Batch No: MMHND / Üretici firma: Gilead Sciences Intl Ltd.) ve Emtricitabin / Tenofovir Disoproxil 200 mg/ 245 mg Film test edilmis olup, 900 mL,de ölçülen dissolüsyon hizi 50 rpm,dir. Örneklerdeki emtrisitabin sodyum asetat ortami/ pH 6.8 fosfat tamponu ortami için hesaplanmistir. (Sekil 5, 6, 7) Biyoesdegerlik Çalismalari (Farmakokinetik) Karboksimetil Selüloz Sodyum ve Magnezyum Stearat orani 1,2: 1-2,0:1 (a/a) araliginda olmak üzere, Tenofovir Disoproksil Fumarat ve Emtrisitabin içeren farmasötik bilesiminin "Truvada" ticari ürün tabletleri karsisinda yapilan biyoesdegerlik çalisma sonuçlari, Tablo 4-5 ve Sekil 8- 9,da gösterilmistir. Etken maddeler olarak Tenofovir ve Emtrisitabin içeren farmasötik bilesim; "(a) % 80 ve % CmaX için % 90 güven araligi" olan biyoesdegerlik parametreleri altinda gönüllülere uygulandiginda, ticari ürün olan Truvada film kapli tabletin karsisinda biyoesdegerlik bulunmustur. Tablo 4: Emtrisitabin / Tenofovir Disoproksil 200 mg / 245 mg Film Tablet - Farmakokinetik Sonuçlari (Emtrisitabin) l SONUÇLAR (EMTRISITABIN) l Parametre Fark Oran 90% C1 CV% Power % Tablo 5: Emtrisitabin / Tenofovir Disoproksil 200 mg / 245 mg Film Tablet - Farmakokinetik Sonuçlari (Tenofovir) l SONUÇLAR (TENOFOVIR) l Parametre Fark Oran 90% C1 CV% Power % Sekillerin Açiklamasi: Sekil 1: Tenofovir DF / Emtrisitabin içerikli film kapli tabletin farmasötik bilesimi için akis semasi Sekil 2: Truvada ve Emtricitabin / karsilastirmali dissolüsyon profili (Çözünme ortami: 0.01 N HCl, (Tenofovir disoproksil) Sekil 3: Truvada ve Emtricitabin / karsilastirmali dissolüsyon profili (Çözünme ortami: pH 4.5 Sodyum Asetat tamponu, 900 mL, Hiz: 50 rpm) (Tenofovir disoproksil) Sekil 4: Truvada ve Emtrisitabin / karsilastirmali dissolüsyon profili (Çözünme ortami: pH 6.8 Fosfat tamponu, 900 mL, Hiz: 50 rpm) (Tenofovir disoproksil) Sekil 5: Truvada ve Emtrisitabin / karsilastirmali dissolüsyon profili (Çözünme ortami: 0.01 N HCl, (Emtrisitabin) Sekil 6: Truvada ve Emtrisitabin / karsilastirmali dissolüsyon profili (Çözünme ortami: pH 4.5 Sodyum Asetat tamponu, 900 mL, Hiz: 50 rpm) (Emtrisitabin) Sekil 7: Truvada ve Emtrisitabin / karsilastirmali dissolüsyon profili (Çözünme ortami: pH 4.5 6.8 Fosfat tamponu, 900 mL, Hiz: 50 rpm) (Emtrisitabin) Sekil 8: Emtrisitabin ortalama plazma konsantrasyonu Sekil 9: Tenofovir ortalama plazma konsantrasyonu Kuru Granül-l Eleme: Tenofovir Disoproksil Fumarat, Kroskarmeloz Sodyum, Mikrokristal Selüloz, Laktoz Monohidrat, Kolloidal Silikon Dioksit Karistirma Eleme: Magnezyum stearat Karistirma Slugging Kuru Granül -2 Eleme: Emtrisitabin, Kroskarmeloz Sodyum, Mikrokristal Selüloz, Prej elatinize Nisasta ve Kolloidal Silikon Dioksit Karistirma l Eleme: Magnezyum stearat l Karistirma Karistirma: Kuru Granül- 1 ve Kuru Granül-2 Eleme: Magnezyum Kari tirma Tablet Basimi Kari tirma Film Kaplama Ambalaj lama Slugging Tenofovir Disoproksil-Karsilastirmali Dissolüsyon Profili ( 120s: 2 +Truvada 200 mg/ 245 mg Film Tablet Emtrisitabin /Tenofovir Disoproksil D 40 (Seri numarasi: MMHND) °\° Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423001) +Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri 0 numarasi: 7423002) Süre (dak.) Tenofovir Disoproksil-Karsilastirmali Dissolüsyon Profili (pH 4.5 Sodyum Asetat tamponu) 100 3 o % â -o-Truvada 200 mg/ 245 mg Film Tablet Emtrisitabin /Tenofovir Disoproksil c\° Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423001) +Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423002) Süre (dak.) 100806040 Emtrisitabin-Karsilastirmali Dissolüsyon Profili (0.01 N HCl) Tenofovir Disoproksil-Karsilastirmali Dissolüsyon Profili (pH 6.8 Fosfat Tamponu) -o-Truvada 200 mg/ 245 mg Film Tablet Emtrisitabin /Tenofovir Disoproksil (Seri numarasi: MMHND) Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423001) +Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423002) -o-Truvada Süre (dak.) Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423001) +Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423002) Süre (dak.) Emtrisitabin-Karsilastirmali Dissolüsyon Profili (pH 4.5 Sodyum Asetat) 40 -o-Truvada 200 mg/ 245 mg Film Tablet Emtrisitabin /Tenofovir Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423001) +Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423002) Süre (dak.) Emtrisitabin-Karsilastirmali Dissolüsyon Profili (pH 6.8 Fosfat Tamponu) 4.* + . .E -O-Truvada 200 mg/245 mg Film Tablet Emtrisitabin/ Q 40 Tenofovir Disoproksil (Seri numarasi: MMHND) o\° Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423001) +Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film 0 Tablet (Seri numarasi: 7423002) Süre (dak.) Emtr'is'ita hîi'i Koma i'itrasy-::iiriu [ngfm L:i Temfuvîr Koma ntrasy-:iinu [ng[m L) 1500- Emti'isitabin Ortalama Plazma Konsantrasvonu [ngfmL] + R: Truvada !Dümgflißmg Filiii Ta hlet [Gilead Science - UK) -i- T: Emtr'is'ita hînfl'eriufmîr Dîsupmksîl !Dümgflißmg Filiii Ta hlet 1500'_ 1000*- Zamari [saati Emtrisitahin Ortalama Plazma Kansantrasyanu [ngfmlli -i T: Emtris'itahinfl'eriufmrîr Dîsupmksîl ZDDmgflilfz-mg Filiii Ta hlet 12 2-1 515 4:: Zaman [saatli Sieving: Tenofovir Disoproxil Fumarate, Croscarmellos Sieving: Emtricitabine, Sodium, Microcrystalline Croscarmellos Sodium, cellulose, Lactose Microcrystalline cellulose, Monohydrate, Pregelatinized Pregelatinized Starch and Starch, Talc and Colloidal Colloidal Silicon Dioxide Silicon Dioxide Sieving: Magnesium stearate ` Sieving: Magnesium stearate ` Shîing \ \ Slugging \ Sieving \ \ Sieving \ Mixing: Dry Granule-l and Dry Granule-Z Sieving: Magnesium Figure 1 Comparative Tenofovir Disoproxil Dissolution Profile ( 100 r ^ ^ ^ ^ 3 +Truvada 200 mg/ 245 mg Film Tablet Emtrisitabin /Tenofovir Disoproksil (Seri °\° Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423001) +Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423002) Figure 2 Comparative Tenofovir Disoproxil Dissolution Profile (pH 4.5 Sodium Acetate buffer) 100 1 3 , g -O-Truvada 200 mg/ 245 mg Film Tablet Emtrisitabin /Tenofovir Disoproksil e\° Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423001) +Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423002) Figure 3 100806040 4› CD 00 Comparative Tenofovir Disoproxil Dissolution Profile (pH 6.8 Phosphate buffer) -o-Truvada 200 mg/ 245 mg Film Tablet Emtrisitabin /Tenofovir Disoproksil (Seri numarasi: MMHND) Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423001) +Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423002) Figure 4 Comparative Emtiricitabin Dissolution Profile (0.01 N HCl ) -o-Truvada Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423001) +Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423002) Figure 5 4› CD 00 Comparative Emtiricitabin Dissolution Profile (pH 4.5 Sodium Acetate) -o-Truvada 200 mg/ 245 mg Film Tablet Emtrisitabin /Tenofovir Disoproksil (Seri numarasi: MMHND) Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423001) +Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423002) Figure 6 Comparative Emtiricitabin Dissolution Profile (pH 6.8 Phosphate buffer) -o-Truvada 200 mg/ 245 mg Film Tablet Emtrisitabin /Tenofovir Disoproksil (Seri numarasi: MMHND) Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423001) +Emtrisitabin /Tenofovir Disoproksil 200 mg/ 245 mg Film Tablet (Seri numarasi: 7423002) Figure 7 Errrtriritahiiie commiiiim Iip'mlii Tenafovir mmntmtim Inai'mTJ Awrigi pliima concinirillinn of immuhlini [ngJ'mL] Figure 8 üverige praiimi conmtrition of tunufmrir tngfmL] 1590 - f* a 12 24 si; 43 bu ?2 Figure 9 TR TR TR DESCRIPTION PHARMACEUTICAL COMPOSITION CONTAINING TENOFOVIR AND EMtricitabine Technical Field to which the Invention Concerns This invention relates to the preparation of a pharmaceutical composition containing tenofovir and emtricitabine. The invention also relates to an improved production process and storage stability using the dry granulation method with relevant excipients. Background of the Invention Human Immunodeficiency Virus (HIV) infection and related diseases are one of the major public health problems in the world. Tenofovir and emtricitabine are used to treat HIV infection. Use of the combination of compounds produces an equivalent antiviral effect or increase in drug efficacy with reduced toxicity. Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI). It blocks the reverse transcriptase activity in HIV infection, this enzyme produced by HIV causes cells to become infected and viruses to multiply. Tenofovir disoproxil fumarate is a prodrug in the form of the fumaric acid salt of tenofovir and is a nucleoside reverse transcriptase inhibitor analogue of adenosine. Tenofovir disoproxil fumarate is a fumarate salt prepared with equivalent amounts of tenofovir disoproxil and fumaric acid. The combination of this drug with other drugs has been prescribed for use in the treatment of HIV infection, as well as in the therapy of Hepatitis B. The chemical name of tenofovir disoproxil fumarate is [[(2R)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate; (E)-but-2-enedioic acid, and its chemical structure is shown below. k/ûvl-°^OÂUJ\ *i ;02" . EHB (1`,on HÇI-ßlc _RH Tenofovir Disoproxil Fumarate Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) used in the treatment of HIV infection in adults. Emtricitabine is a cytidine analog. Emtricitabine The chemical class is Nucleoside Analog. The drug works by inhibiting HIV reverse transcriptase, preventing the transcription of HIV from RNA to DNA. The chemical name of emtricitabine is 4-amino-5-Iloro-1-[(2R,5S)-2-(hydroxymethyl) It is -1,3-oxathiolane- -yl]pyrimidin-2-one and its chemical structure is shown below. attigi" M ;CH Emtricitabine Tenofovir Disoproxil Fumarate / Emtricitabine is available in the market in film-coated tablet composition. 245 mg / 200 mg. It is administered orally at therapeutic doses and is used in the treatment of HIV infection in adults. Tenofovir Disoproxil Fumarate/Emtricitabine is marketed by GILEAD under the trademark Truvada® in 245/200 mg dosage forms. It is used to prevent immune deficiency against the proliferation of the HIV virus in the human body. It is used to treat Acquired Immune Deficiency Syndrome (AIDS), which can be caused by the HIV virus. Truvada®; Contains croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose and pregelatinized starch (gluten-free). Emtricitabine and Tenofovir Disproxil Fumaratain immediate-release tablets were formulated and evaluated using different distributors. The main purpose of this study is; This is the formulation and evaluation of the immediate release tablet containing Emtricitabine and Tenofovir Disproxil Fumarate using different dispensers. This work; (Manikandan M., Kannan K.*, Selvamuthukumar S. and Manavalan R., Composition development and evaluation of Emtricitabine and Tenofovir Disproxil Fumarate Tablets, International Journal of Drug Development & Research. January-March 2012 | Vol. 4 | Issue 1) It was carried out based on the scientific article named. EP1890681 A2 relates to a pharmaceutical composition of Emtricitabine/Tenofovir DFa, obtained by dry granulation of the components Tenofovir DF and Emtricitabine in a pharmaceutically acceptable excipient. EP3326619 A1 relates to a pharmaceutical composition for the treatment of HIV-1 and hepatitis B, containing the active ingredients Tenofovir/Emtricitabine and a starchless excipient. The tablet composition is prepared by wet granulation. WO20 1 5 085 976Al relates to a stable pharmaceutical composition for the preparation of tablets by wet granulation comprising Tenofovir Disoproxil Fumarate or the combination of Tenofovir Disoproxil Fumarate with another active ingredient and a disintegrant. Instead of croscarmellose sodium; selecting a disintegrant from the group of crospovidone, corn starch and hydroxypropyl cellulose, the conversion of Tenofovir Disoproxil Fumarate to Tenofovir Disoproxil Hemifumarate or the combination of a pharmaceutically acceptable salt of Emtricitabine and Efavirenz or a pharmaceutically acceptable salt of Efavirenz. The process is carried out by wet granulation. Summary of the Invention The present invention relates to the preparation of a pharmaceutical composition containing Tenofovir Disoproxil Fumarate and Emtricitabine for use in the treatment of HIV infection. The present invention is related to the pharmaceutical composition containing Tenofovir Disoproxil Fumarate and Emtricitabine prepared for use in the treatment of HIV infection and involves the production of this composition by dry granulation method. The present invention relates to a pharmaceutical composition containing Tenofovir Disoproxil Fumarate, Emtricitabine, Croscarmellose Sodium and Magnesium Stearate, and the mass composition ratio of croscarmellose sodium and magnesium stearate in the total tablet composition is in the range of 1.2: l-2.0: l (w/w). is to be. For the specified composition, the mass composition ratio of croscarmellose sodium and magnesium stearate in the total tablet composition is 1.2:1-2.0:l (w/w), primarily 1.4:1-1.8:l (w/w), further When it is primarily in the range of 1.5:1-1.6:1 (a/w); It was observed that the composition had a synergistic effect on the dissolution profile and bioavailability. Detailed Description of the Invention The present invention relates to the preparation of a pharmaceutical composition containing Tenofovir Disoproxil Fumarate and Emtricitabine for use in the treatment of HIV infection related to the virus that may cause Acquired Immune Deficiency Syndrome (AIDS). Depending on the water used in wet granulation and the heat factors used in the drying process, the active ingredients Tenofovir and Emtricitabine are degraded through hydrolysis. The use of organic solvents (isopropyl alcohol, ethanol) in wet granulation involves potential environmental risk factors and process costs. For this reason, dry granulation is preferred as the production method. The main purpose of the present invention is to obtain a stable tablet composition containing Tenofovir DF and Emtricitabine by dry granulation method. In this process, the dry granulation method is used instead of the wet granulation process involving water and heat, which is the main cause of the degradation (hydrolysis) of active substances. Dry granulation used in this process occurs faster than wet granulation. Another purpose; The aim is to provide an improved production process that is simple, cost-effective and time-saving to prepare a film-coated tablet composition in the composition of Tenofovir Disoproxil Fumarate and Emtricitabine. In this process, dry granulation has many advantages over wet granulation. Due to the use of the dry granulation method, the flow chart results in a very cost-effective composition. The present invention presents a new composition of Tenofovir Disoproxil Fumarate and Emtricitabine, as described in the claims, which overcomes the problems defined in the state of the art and provides additional advantages to the state of the art. Another purpose; The pharmaceutical composition containing Tenofovir Disoproxil Fumarate, Emtricitabine and excipients has bioequivalence and stability throughout shelf life. Another purpose of the present invention is; Our aim is to obtain combination compositions of Tenofovir DF and Emtricitabine with high stability and bioavailability. Another aim of the present invention is to obtain combination compositions of Tenofovir DF and Emtricitabine with improved solubility rate and dissolution. When the mass combination ratio of croscarmellose sodium and magnesium stearate was in the range of 1.2:1-2.0:l (w/w) in the total tablet composition, a synergistic effect was observed in the dissolution and bioequivalence study results. Another purpose of the present invention is to have two different stages: Dry granule-1 and dry granule-2. Tenofovir Disoproxil Fumarate is added in the Dry granule-1 stage, while Emtricitabine is added in the Dry granule-2 stage. After these steps are carried out separately, Dry granule-1 and Dry granule-2 are mixed with each other. Following the mixing step, tablet printing, film coating and packaging steps are carried out. Present invention; It discloses a pharmaceutical composition for the treatment of HIV infection comprising Tenofovir Disoproxil Fumarate, Emtricitabine, Croscarmellose Sodium and Magnesium Stearate, wherein the mass ratios of croscarmellose sodium and magnesium stearate are in the range of 1.2:1-2.0:1 (w/w), primarily It is in the range of l,4:l-l,8:l (w/w), and primarily in the range of l,5:l-l,6:l (w/w). The present invention further provides a pharmaceutical composition comprising Tenofovir Disoproxil Fumarate and Emtricitabine; a) tenofovir disoproxil fumarate granules are prepared as dry granules-1 by the dry granulation method, b) emtricitabine granules are prepared as dry granules-2 by the dry granulation method, c) contain croscarmellose sodium and magnesium stearate as excipients, wherein the total of croscarmellose sodium and magnesium stearate The ratio in the tablet composition is 1.2:1-2.0:l (w/w), primarily 1.4:1-1.8:l (w/w), primarily 1.5:1-1.6:l (w/w). a) is in the range. In one respect, in composition; At least one pharmaceutically acceptable excipient selected from the group consisting of disintegrants, diluents, binders, lubricants and glidants may be present. The composition may contain Microcrystalline Cellulose and Pregelatinized Starch as disintegrants and/or binders. The composition may contain Lactose Monohydrate as a diluent. The composition may contain Colloidal Silicon Dioxide and Talc as glidants. The composition of the present invention may be in any solid oral dosage form. The preferred dosage form in accordance with the present invention is the tablet, more preferably the film-coated tablet. Diluents may be water-soluble or water-insoluble. Diluents; cellulose derivatives including, but not limited to, spray dried (SD) or anhydrous lactose, lactose monohydrate, sucrose, dextrose, starch, pregelatinized starch, mannitol, maltitol, sorbitol, xylitol, dextrin, powdered cellulose, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium. phosphate and calcium sulfate, kaolin, precipitated calcium carbonate, maltodextrin and other similar substances in the prior art. Preferred diluents are lactose (SD) and/or lactose monohydrate and/or microcrystalline cellulose. A mixture of diluents may also be used. Bindings; including, but not limited to, methylcellulose, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, silified microcrystalline cellulose, polyvinyl pyrrolidone, gelatin, polyvinyl alcohol, gum arabic, tragacanth, guar, pectin, starch starch, pregelatinized starch, It may be selected from a group including alginic acid, compressible sugar, liquid glucose, dextrates, dextrin, dextrose, maltodextrin, guar resin, magnesium aluminum silicate, polymethacrylate, sorbitol, sucralose and other similar substances in the prior art. The preferred binder is pregelatinized starch. A mixture of binders can also be used. Distributors; including, but not limited to, alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose, carboxymethyl cellulose sodium, cross-linked sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar resin, magnesium aluminum silicate, microcrystalline cellulose, methyl cellulose. oz, polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidones, polyacrylin potassium, starch, pregelatinized starch, sodium alginate, sodium lauryl sulfate, sodium starch glycolate, crystalline cellulose, hydroxypropyl starch and other similar substances in the prior art. A combination of the distributors mentioned here can also be used. The preferred dispersant is croscarmellose sodium and lactose monohydrate. A mixture of dispersants can also be used. Lubricants; including, but not limited to, vegetable oils such as hydrogenated vegetable oil or hydrogenated castor oil, polyethylene glycols such as polyethylene glycol (PEG)-4000 and PEG-6000, stearic acid, magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate and stearic acid derivatives such as sodium stearyl fumarate, mineral salts such as talc, inorganic salts, organic salts such as sodium benzoate, sodium acetate, sodium chloride and sodium oleate, and polyvinyl alcohols, microcrystalline cellulose, sodium lauryl sulfate, silica, colloidal silica, corn starch, It may be selected from a group consisting of calcium silicate, magnesium silicate, silicone hydrogel and other similar materials in the prior art. The preferred lubricant is magnesium stearate. A mixture of lubricants can also be used. Glidants; including, but not limited to, colloidal silicon dioxide, colloidal silica, corn starch, talc, calcium silicate, magnesium silicate, magnesium trisilicate, amorphous silica, colloidal silicon, silicone hydrogel, powdered cellulose, silicon dioxide, talc, tribasic calcium phosphate and prior art materials. It may be selected from a group containing other similar substances. Preferred glidants are colloidal silicon dioxide and talc. A mixture of glidants can also be used. Fillers; including, but not limited to, calcium carbonate, calcium phosphate, calcium sulfate, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, compressible sugar, powdered sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil oil-type l, kaolin, lactose, lactose monohydrate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylate, potassium chloride, powdered cellulose, corn starch, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar The spheres may be selected from a group including talc, tribasic calcium phosphate, xylitol and other similar substances in the prior art. The preferred filler is lactose monohydrate. A mixture of fillers can also be used. Film coating agent; It may be selected from a group including, but not limited to, hydroxypropyl cellulose, hydroxymethyl cellulose, ethyl cellulose, talc, polyethylene glycol, titanium dioxide, lactose monohydrate, yellow iron oxide, triacetin and other similar substances in the prior art. A mixture of film coating agents can also be used. Dry granule-1 containing Tenofovir Disoproxil Fumarate granule can be prepared by going through the following steps; a. Elimination of Tenofovir Disoproxil Fumarate, Croscarmellose Sodium, Microcrystalline Cellulose, Lactose Monohydrate, Pregelatinized Starch, Talc and Colloidal Silicon Dioxide Mixing of components Sieving Magnesium Stearate, Mixing of components Slugging Elimination of all excipients Dry granule-2 containing Emtricitabine granule can be prepared by following steps ; a. Elimination of Emtricitabine, Croscarmellose Sodium, Microcrystalline Cellulose, Pregelatinized Starch and Colloidal Silicon Dioxide c. Elimination of Magnesium Stearate e. Slugging The present invention also includes the process consisting of the following steps regarding the preparation of the pharmaceutical composition; Mixing of Dry granule-1 and Dry granule-2, Sieving of Magnesium Stearate, Mixing of the components, Tablet pressing, Mixing, Film coating, Packaging. The present invention covers the pharmaceutical composition characterized as follows, containing Tenofovir Disoproxil Fumarate, Emtricitabine and related excipients; i) Appropriate stability ii) Programming the release of the active substance with the desired therapeutic effects iii) Simple and competitive manufacturing process. Function and selection of excipients in the composition; In one respect, the process of preparing the tablet composition containing Tenofovir Disoproxil Fumarate and Emtricitabine may include the following steps; (Figure 1) Dry granule-1 a. Screening: Tenofovir Disoproxil Fumarate, Croscarmellose Sodium, Microcrystalline Cellulose, Lactose Monohydrate, Pregelatinized Starch, Talc and Colloidal Silicon Dioxide, b. Mixing c. Magnesium Stearate elimination d. mixing the components of steps a and c e. Slugging Dry granule-2 g. Elimination: Emtricitabine, Croscarmellose Sodium, Microcrystalline Cellulose, Pregelatinized Starch and Colloidal Silicon Dioxide, h. mixing of the components in step g i. Sifting Magnesium Stearate Mixing the components in the g and i stages k. Slugging . Mixing of Dry granule-1 and Dry granule-2. Tablet pressing. Film coating. Packaging. Compositions of the present invention can be used in the treatment of HIV. The present invention also includes a pharmaceutical composition for the treatment of HIV such as; Table 1: Final composition of Tenofovir DF / Emtricitabine film-coated tablet (245mg/200mg) Unit Formula Tenofovir Disoproxil Fumarate Active Ingredient 300.00 29.85 Emtricitabine Active Ingredient 200.00 19.90 Croscarmellose Sodium Diffuser 40.00 3.98 Microcrystalline Cellulose Binder, Dispersant N/A N/A Lactose Monohydrate Diluent N/A N/A Pregelatinized Starch Binder, Dispersant N/A N/A Colloidal Silicon Dioxide Lubricant N/A N/A Talc Lubricant N/A N/A Magnesium Stearate Glidant 25,00 2, 49 Core Tablet N/A N/A Opadry II Light Blue Y-30-10671-A Film Coating Material N/A N/A Distilled water Solvent N/A N/A Film Coated Tablet N/A 100,00 Opadry II Light Blue Y- 30-10671-A Content Amount (%, w/w) Lactose Monohydrate 40.00 Titanium Dioxide 22.51 Triacetin 8.00 Fd&C Blue #2/Indigo Carmine Aluminum Lake (3-5%) 1.49 Dissolution and Bioequivalence Studies Pharmaceutical composition containing Tenofovir Disoproxil Fumarate and Emtricitabine; Carboxymethyl Cellulose Sodium and Magnesium Stearate were used in the range of 1.2:1-2.0:1 (w/w). Dissolution and Pivotal Bioequivalence study results; Carboxymethyl Cellulose Sodium and Magnesium Stearate gave satisfactory results when used in the range of 1.2:1-2.0:1 (w/w). In-vitro Studies for Final Composition Carboxymethyl Cellulose Sodium and Magnesium Stearate In-vitro study results for the pharmaceutical composition containing Tenofovir Disoproxil Fumarate and Emtricitabine are given below, in the range of 1.2: 1-2.0:1 (w/w). The final tablet composition is shown in Table 1. Table 2: Comparative Dissolution Profiles of Emtricitabine / Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablets (0.01 N HCl medium / pH 4.5 sodium phosphate medium / pH 6.8 phosphate buffer medium) (Tenofovir Disoproxil) 0.01 N HCl medium pH 4.5 sodium phosphate pH 6.8 phosphate buffer environment environment Tenofovir Disoproxil Tenofovir Disoproxil Tenofovir Disoproxil Average % Dissolution Average % Dissolution Average % Dissolution Time (Emtricitabine / T enofovir (Emtricitabine / T enofovir (Emtricitabine / T enofovir mg Film Tablet) mg Film Tablet) mg Film Tablet) The mentioned in the present invention pharmaceutical composition; "Emtricitabine / Tenofovir Disoproxil 200 mg / 245 mg Film-coated Tablet [Truvada 200 mg / 245 mg Film-coated Tablet (Batch No: MMHND / Manufacturer: Gilead Sciences Intl Ltd.) and Emtricitabine / Tenofovir Disoproxil 200 mg / 245 mg Film-coated Tablet have been tested and The dissolution rate measured in 900 mL is 50 rpm. It was calculated for tenofovir / pH 4.5 sodium phosphate medium / pH 6.8 phosphate buffer medium in the examples (Figures 2, 3, Table 3: Emtricitabine / Tenofovir Disoproxil 200 mg / 245 mg Film-coated Tablets Comparative Dissolution Profiles (0.01 N HCl medium / pH 4.5 sodium acetate medium / pH 6.8 phosphate 0.01 N HCl medium pH 4.5 sodium acetate pH 6.8 phosphate buffer medium medium Emtricitabine Average Emtricitabine Average Emtricitabine Average % Time (Emtricitabine / T enofovir (Emtricitabine / T enofovir) (Emtricitabine / Tenofovir mg Film Tablet) mg Film Tablet) Film Tablet) The pharmaceutical composition mentioned in the present invention; "Emtricitabine / Tenofovir Disoproxil 200 mg / 245 mg Film Tablet [Truvada 200 mg / 245 mg Film Tablet (Batch No: MMHND / Manufacturer: Gilead Sciences Intl Ltd.) and Emtricitabine / Tenofovir Disoproxil 200 mg/ 245 mg Film were tested, and the dissolution speed measured in 900 mL was 50 rpm. The emtricitabine in the examples was calculated for sodium acetate medium/pH 6.8 phosphate buffer medium. (Figure 5, 6, 7) Bioequivalence Studies (Pharmacokinetics) "Truvada" is a pharmaceutical composition containing Tenofovir Disoproxil Fumarate and Emtricitabine, with the ratio of Carboxymethyl Cellulose Sodium and Magnesium Stearate in the range of 1.2: 1-2.0:1 (w/w). The bioequivalence study results against commercial product tablets are shown in Tables 4-5 and Figures 8-9. Pharmaceutical composition containing Tenofovir and Emtricitabine as active ingredients; Bioequivalence was found versus the commercial product Truvada film-coated tablet when administered to volunteers under bioequivalence parameters of "(a) 80% and 90% confidence interval for Cmax". Table 4: Emtricitabine / Tenofovir Disoproxil 200 mg / 245 mg Film-coated Tablet - Pharmacokinetic Results (Emtricitabine) l RESULTS (EMTRISITABIN) l Parameter Difference Ratio 90% C1 CV% Power % Table 5: Emtricitabine / Tenofovir Disoproxil 200 mg / 245 mg Film-coated Tablet - Pharmacokinetic Results (Tenofovir) l RESULTS (TENOFOVIR) l Parameter Difference Ratio 90% C1 CV% Power % Explanation of Figures: Figure 1: Flow chart for the pharmaceutical composition of film-coated tablet containing Tenofovir DF / Emtricitabine Figure 2: Truvada and Emtricitabine / comparative dissolution profile (Dissolution medium: 0.01 N HCl, (Tenofovir disoproxil) Figure 3: Truvada and Emtricitabine / comparative dissolution profile (Dissolution medium: pH 4.5 Sodium Acetate buffer, 900 mL, Speed: 50 rpm) (Tenofovir disoproxil) Figure 4: Truvada and Emtricitabine / comparative dissolution profile (Dissolution medium: pH 6.8 Phosphate buffer, 900 mL, Speed: 50 rpm) (Tenofovir disoproxil) Figure 5: Truvada and Emtricitabine / comparative dissolution profile (Dissolution medium: 0.01 N HCl, (Emtricitabine) Figure 6: Truvada and Emtricitabine / comparative dissolution profile (Dissolution medium: pH 4.5 Sodium Acetate buffer, 900 mL, Speed: 50 rpm) (Emtricitabine) Figure 7: Truvada and Emtricitabine / comparative dissolution profile (Dissolution medium: pH 4.5 6.8 Phosphate buffer, 900 mL , Speed: 50 rpm) (Emtricitabine) Figure 8: Mean plasma concentration of Emtricitabine Figure 9: Mean plasma concentration of Tenofovir Dry Granule-l Elimination: Tenofovir Disoproxil Fumarate, Croscarmellose Sodium, Microcrystalline Cellulose, Lactose Monohydrate, Colloidal Silicon Dioxide Mixing Elimination: Magnesium stearate Mixing Slugging Dry Granule -2 Sieving: Emtricitabine, Croscarmellose Sodium, Microcrystalline Cellulose, Pregelatinized Starch and Colloidal Silicon Dioxide Mixing Sieving: Magnesium stearate l Mixing Mixing: Dry Granule-1 and Dry Granule-2 Sieving: Magnesium Mixing Tablet Pressing Kar Film Coating Packaging Slugging Tenofovir Disoproxil-Comparative Dissolution Profile ( 120s: 2 +Truvada 200 mg/ 245 mg Film Tablet Emtricitabine / Tenofovir Disoproxil D 40 (Serial number: MMHND) °\° Emtricitabine / Tenofovir Disoproxil 200 mg/ 245 mg Film Tablet (Serial number: 7423001) +Emtricitabine /Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet (Series 0 number: 7423002) Time (min.) Tenofovir Disoproxil-Comparative Dissolution Profile (pH 4.5 Sodium Acetate buffer) 100 3 o % â - o-Truvada 200 mg/ 245 mg Film-coated Tablet Emtricitabine / Tenofovir Disoproxil c\° Emtricitabine / Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet (Serial number: 7423001) +Emtricitabine / Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet (Serial number: 7423002) Time (min.) 100806040 Emtricitabine-Comparative Dissolution Profile (0.01 N HCl) Tenofovir Disoproxil-Comparative Dissolution Profile (pH 6.8 Phosphate Buffer) -o-Truvada 200 mg/ 245 mg Film-coated Tablet Emtricitabine /Tenofovir Disoprok delete (Serial number: MMHND ) Emtricitabine / Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet (Serial number: 7423001) mg / 245 mg Film-coated Tablet (Serial number: 7423001) Truvada 200 mg/ 245 mg Film-coated Tablet Emtricitabine /Tenofovir Emtricitabine /Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet (Serial number: 7423001) +Emtricitabine /Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet (Serial number: 7423002) Duration (min. ) Emtricitabine-Comparative Dissolution Profile (pH 6.8 Phosphate Buffer) 4.* + . . E -O-Truvada 200 mg/245 mg Film-coated Tablet Emtricitabine/ Q 40 Tenofovir Disoproxil (Serial number: MMHND) o\° Emtricitabine /Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet (Serial number: 7423001) mg/ 245 mg Film 0 Tablet (Serial number: 7423002) Duration (min.) Emtr'is'ita hîi'i Koma i'itrasy-::iiriu [ngfm L:i Temfuvîr Koma ntrasy-:iinu [ng[m L ) 1500- Mean Plasma Concentration of Emti'isitabine [ngfmL] + R: Truvada! Dümgflißmg Filiii Ta hlet [Gilead Science - UK) -i- T: Emtr'is'ita hînfl'eriufmîr Dîsupmksîl! Dümgflißmg Filiii Tahlet 1500'_ 1000*- Time disoproxil Fumarate, Croscarmellos Sieving: Emtricitabine, Sodium, Microcrystalline Croscarmellos Sodium, cellulose, Lactose Microcrystalline cellulose, Monohydrate, Pregelatinized Pregelatinized Starch and Starch, Talc and Colloidal Colloidal Silicon Dioxide Silicon Dioxide Sieving: Magnesium stearate ` Sieving: Magnesium stearate ` Shîing \ \ Slugging \ Sieving \ \ Sieving \ Mixing: Dry Granule-l and Dry Granule-Z Sieving: Magnesium Figure 1 Comparative Tenofovir Disoproxil Dissolution Profile ( 100 r ^ ^ ^ 3 +Truvada 200 mg/ 245 mg Film Tablet Emtricitabine / Tenofovir Disoproxil (Series ° \ ° EMTRISITABINE / TENofovir Disoproxyl 200 mg / 245 mg Film Tablet (Serial Number: 7423001) +Egtrisitabin / Tenofovir Disoproxyl 200 mg / 245 mg Film Tablet (Serial Number: 7423002) ffer ) 100 1 3 , g -O-Truvada 200 mg/ 245 mg Film-coated Tablet Emtricitabine / Tenofovir Disoproxil e\° Emtricitabine / Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet (Serial number: 7423001) mg Film-coated Tablet (Serial number: 7423002) Figure 3 100806040 4› CD 00 Comparative Tenofovir Disoproxil Dissolution Profile (pH 6.8 Phosphate buffer) -o-Truvada 200 mg/ 245 mg Film-coated Tablet Emtricitabine /Tenofovir Disoproxil (Serial number: MMHND) Emtricitabine / Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet (Serial number: 7423001) Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet (Serial number: 7423001) o-Truvada 200 mg/ 245 mg Film-coated Tablet Emtricitabine / Tenofovir Disoproxil (Serial number: MMHND) Emtricitabine / Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet (Serial number: 7423001) +Emtricitabine / Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet ( Serial number: 7423002) Figure 6 Comparative Emtricitabine Dissolution Profile (pH 6.8 Phosphate buffer) -o-Truvada 200 mg/ 245 mg Film-coated Tablet Emtricitabine /Tenofovir Disoproxil (Serial number: MMHND) Emtricitabine /Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet ( Serial number: 7423001) +Emtricitabine /Tenofovir Disoproxil 200 mg/ 245 mg Film-coated Tablet (Serial number: 7423002) Figure 7 ge praiimi conmtrition of tunufmrir tngfmL] 1590 - f* a 12 24 si; 43 this ?2 Figure 9 TR TR TR
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