TR2024014829A2

TR2024014829A2 - COMPOSITIONS CONTAINING MEMANTINE AND DONEPEZIL

Info

Publication number: TR2024014829A2
Application number: TR2024/014829
Authority: TR
Inventors: Dehan Kesg N D; Mazinli Alper; Urcan Kartal U
Original assignee: Ardi̇ Farma İlaç Pazarlama Ti̇caret Li̇mi̇ted Şi̇rketi̇
Filing date: 2024-10-31
Publication date: 2024-11-21

Abstract

Mevcut Buluş, farmasötik teknoloji alanı ile ilgilidir ve uzun salımlı memantin veya farmasötik olarak kabul edilebilir tuzunu içeren tablet ve hızlı salımlı donepezil veya farmasötik olarak kabul edilebilir tuzunu içeren tablet içeren kapsül kompozisyonu ile ilgilidir.The present invention relates to the field of pharmaceutical technology and relates to a capsule composition comprising a tablet containing extended-release memantine or a pharmaceutically acceptable salt thereof and a tablet containing immediate-release donepezil or a pharmaceutically acceptable salt thereof.

Description

TARIFNAME MEMANTIN VE DONEPEZIL IÇEREN KOMPOZISYONL Teknik Alan Mevcut Bulus, farmasötik teknoloji alani ile ilgilidir ve uzun salimli memantin veya farmasötik olarak kabul edilebilir tuzunu içeren tablet ve hizli salimli donepezil veya farmasötik olarak kabul edilebilir tuzunu içeren tablet içeren kapsül kompozisyonu ile Önceki Teknik Memantin HCl 3,5-dimetiladamantan-1-amin hidroklorür kimyasal ismiyle bilinen bir etken maddedir ve kimyasal yapisi asagida yer almaktadir: H 1 : `H ,x * : h" Formül 1 Molekül formülü C12H21N.HCl,dir ve molekül agirligi 215.77 mgadir. Molekül suda çözünür. Yüksek çözünürlük ve yüksek permabilitesi ile BCS sinif 1 moleküldür. Memantin HCl orta-agir Alzheimer hastaliginin semptomatik tedavisinde hem monoterapi olarak hem de bir kolinesteraz inhibitörü (ChEI) olan donepezil ile birlikte kullanilan bir N- metil-D-aspaitat (NMDA) reseptör antagonistidir. Amerika Birlesik Devletleriande mg uzatilmis salimli kapsüller) olarak bulunmaktadir. Ayrica Avrupa,da Ebixa® (10 mg ve mg film kapli tabletler) olarak da bulunmaktadir. Donepezil HCl (±)-2-[(1-Benzil-4-piperidil)metil]-5,6 dimetoksi-1-indanon hidroklorür kimyasal ismiyle bilinen bir etken maddedir ve kimyasal yapisi asagida yer almaktadir: Formül 2 çözünür. Yüksek çözünürlük ve yüksek permabilitesi ile BCS sinif 1 moleküldür. Donepezil HCl hafif ila siddetli Alzheimer hastaliginin semptomatik tedavisi için onaylanmis bir piperidin tipi tersinir kolinesteraz inhibitörüdür. Piyasada 5 mg, 10 mg ve 23 mg film kapli tabletler ile 5 mg ve 10 mg agizda dagilan tabletler halinde bulunmaktadir. Orta ve siddetli Alzheimer tipi demansin tedavisinde endike olan donepezil ve memantin kombinasyonu ise, piyasada Namzaric® ticari adi ile bulunmaktadir. Namzaric uzatilmis salimli kapsül formundadir. Ayrica her iki etken maddeyi de içeren hizli salimli film kapli tabletler de piyasalarda bulunmaktadir. Teknigin bilinen durumunda, memantine ve donepezil kombinasyonlari ile ilgili farkli patentler bulunmaktadir. H. LUNDBECK A/Saye ait EP1509232 Bl patenti, Memantin ve Donepezil içeren uzatilmis salim formülasyonu ile ilgilidir. Içinde etkili miktarda bir veya birden fazla asetilkolinesteraz inhibitörü/inhibitörleri veya bunlarin farmasötik olarak etkili tuzlari ve etkili miktarda bir veya birden fazla NMDA-antagonisti/antagonistleri bulunan farmasötik bilesim açiklanmaktadir. ADAMAS PHARMACEUTICALS, INCfe ait EP1874282 Bl patenti, Alzheimer hastaligi gibi MSS ile iliskili hastaliklarin tedavisinde kullanilacak bilesimlere iliskindir. Memantin ve Donepezil içeren uzatilmis salim formülasyonlari açiklanmaktadir. Forest Laboratories, Incfe ait EP1781261 A1 patenti, uzatilmis salimli memantin formülasyonu ile ilgilidir. Salim kontrol ajani içeren uzatilmis salimli memantin tablet formülasyonu açiklanmaktadir. memantin veya memantinin kabul edilebilir bir tuzunu kombinasyon halinde içeren oral dozaj formülasyonu ile ilgilidir. Ilgili formülasyonda intragranüler faZda misir nisastasi ve mikrokristalin selüloz pH 102 kullanilmistir. Lupin,e ait TR 2020/21642 patenti, uzatilmis salimli donepeZil formülasyonlari ile ilgilidir. Ali Raif" e ait TR 2011/04108 patenti, uzatilmis salim saglayan ve hemen salim saglayan iki kisimdan olusan memantin formülasyonlari ile ilgilidir. Teknigin önceki durumunda memantin veya memantinin farmasötik olarak kabul edilebilir bir tuzunu ve/Veya donepeZil veya donepeZilin farmasötik olarak kabul edilebilir bir tuzunu içeren oral farmasötik dozaj formlarinin ortaya kondugu yukarida açiklanan patentler bulunmaktadir. Bununla birlikte, teknikteki formülasyonlardan hem memantin etken maddesini içeren hem de donepeZil etken maddesini içeren patentler üretim maliyetinin çok yüksek oldugu bilinen pellet teknigi ile üretilen formülasyonlar ya da ilacin üretim maliyetini aitirabilecek ve uygulamasi güç karmasik teknikleri içeren formülasyonlar ile ilgilidir. Bu nedenle, önceki teknikte yukarida açiklanan sorunlari ortadan kaldiran ve bunlara ek avantajlar getiren, memantin veya memantinin farmasötik olarak kabul edilebilir bir tuzunu ve donepeZil veya donepeZilin kabul edilebilir bir tuzunu içeren bir kompozisyonlara hala ihtiyaç bulunmaktadir. Sekillerin açiklamasi: Sekil 1. Namzaric® 28 mg/ 10 mg mg XR Kapsül -Formül 1 dissolüsyon grafigi-Memantin Sekil 2. Namzaric® 28 mg/ 10 mg mg XR Kapsül -Formül 1 dissolüsyon grafigi-Donepezil Bulusun Kisa Açiklamasi Mevcut bulus, asagidaki örneklerde ve istemlerde daha ayrintili biçimde ifade edildigi üzere, hem kontrollü salim saglayan tablet hem de hizli salim saglayan tablet içeren kapsül seklinde gelistirilen formülasyonu ve bu formülasyonun hazirlanma yöntemini açiklamaktadir. Mevcut bulus, kontrollü salim saglayan tablet kisminda etken madde olarak veya memantinin farmasötik olarak kabul edilebilir bir tuzunu içermektedir. Tercihen Memantin HCl tuzunu içermektedir. Mevcut bulus, hizli salim saglayan tablet kisminda Donepezil veya donepezilin farmasötik olarak kabul edilebilir bir tuzunu içermektedir. Tercihen Dopenezil HCl tuzunu içermektedir. Mevcut bulus, kontrollü salim saglayan tablet olarak tercihen 7 mg, 14mg, 21 mg veya 28 mg Memantin HCl ve hizli salim saglayan tablet olarak tercihen 10 mg Donepezil HCl içermektedir. Mevcut bulusta, dört farkli Memantin HCl dozu içeren kapsüller gelistirilmistir. Mevcut bulus ile, pellet üretiminden kaynaklanan üretim maliyetlerinden ve olusan firelerden uzaklasilmistir. Tek bir tablet formülasyonunun üretimi ile 4 farkli dozda uzatilmis salimli memantin HCl içeren bitmis ürün elde edilebilmistir. Bu sayede, her doz için (örnegin 7 mg, 14 mg, 21 mg veya 28 mg Memantin HCl dozlari için) farkli formülasyon hazirlanmasi gerekliligini ortadan kaldirilmistir. Mevcut bulus ile yukarida bahsedilen problemlerin üstesinden gelinmis ve referans ürün ile karsilastirmali biyoesdegerlik çalismalari yaptirilarak uygun sonuçlar alinmistir. Bulusun Detayli Açiklamasi Mevcut bulus, hem kontrollü salim saglayan tablet hem de hizli salim saglayan tablet içeren kapsül formunda farmasötik kompozisyon olup, kontrollü salim saglayan tablette etkin madde olarak Memantin veya farmasötik olarak kabul edilebilir bir tuzunu içeren, hizli salimli tablette etken madde olarak Donepezil veya farmasötik olarak kabul edilebilir bir tuzunu içeren formülasyon ile ilgilidir. Memantinin farmasötik olarak kabul edilebilir bir tuzu tercihen Hidroklorür tuzudur. Donepezilin farmasötik olarak kabul edilebilir bir tuzu tercihen Hidroklorür tuzudur. Mevcut bulus, 28 mg, 21 mg, 14 mg veya 7 mg Memantin HCl tablet içeren kapsül formunda kontrollü salim saglayan farmasötik kompozisyonlar ile ilgilidir. Mevcut bulus, 10 mg Donepezil HCl tablet içeren kapsül formunda hizli salim saglayan farmasötik kompozisyonlar ile ilgilidir. Mevcut bulusta, iki farkli tablet kompozisyonu hazirlanmaktadir. Bunlardan biri uzun salimli, enterik kapli Memantin HCl tabletler, digeri hizli salimli donepezil HCl tabletlerdir. Memantin veya farmasötik olarak kabul edilebilir bir tuzunu içeren tabletler üç asamada hazirlanmaktadir. Birinci asamada salim kontrol ajani içeren çekirdek tabletler hazirlanir. Ikinci asamada enterik bir aj anla tabletlere enterik kaplama yapilir. Üçüncü asamada ise kapli tabletler kapsüllenmektedir. Memantinin tercih edilen tuzu HCl tuzudur. Donepezil veya farmasötik olarak kabul edilebilir bir tuzunu içeren tabletler iki asamada hazirlanmaktadir. Birinci asamada çekirdek tabletler hazirlanir. Ikinci asamada ise tabletler kapsüllenmektedir. Donepezilin tercih edilen tuzu HCl tuzudur. Mevcut bulusta, Memantin HCl içeren kapsül içi uzun salimli tabletler salim kontrol ajanlari, dolgu maddesi, seyreltici, baglayici madde ve kaydirici ajanlarin en az birini veya bunlarin Mevcut bulus, Memantin HCl tablet kisminda, kontrollü salim ajani olarak polietilen oksit, polivinil pirolidin, hidroksipropil selüloz, hidroksipropil metil selüloz, vinil asetat kopolimerleri, karbomer, polisakaritler (aljinat, ksantan zamki, karagin vb.) veya bunlarin türevleri ve karisimlarindan seçilir. Daha tercihen, seçilen polimer hidroksipropil metil selülozdur. Salim kontrol ajani olarak kullanilan hidroksipropil metil selülozun uzun salimli tablet içerigine orani, tercihen agirlikça %40-90 arasindadir. Daha tercihen agirlikça %50-70 arasindadir. Mevcut bulusta, kapsül içi uzun salimli tabletler karbomer, karboksimetilselüloz sodyum, dekstrin, dekstroz, maltodekstrin, jelatin, hidroksietil selüloz, hidroksietilmetil selüloz, hidroksipropil selüloz, düsük sübstitüe hidroksipropil selüloz, etilselüloz, metilselüloz, hipromeloz, polivinil pirolidon, magnezyum alüminyum silikat, metil selüloz, sodyum aljinat, nisasta, prejelatinize nisasta, kopovidon ve bunlarin herhangi bir kombinasyonundan olusan gruptan seçilen en az bir baglayici ihtiva eder. Mevcut bulusta, kapsül içi uzun salimli tabletler baglayici olarak polivinil pirolidon içermektedir. Baglayici ajan olarak kullanilan polivinil pirolidonun uzun salimli tablet içerigine orani, tercihen agirlikça %0.5-10 arasindadir. Daha da tercihen agirlikça %1-5 arasindadir. Bulus konusu farmasötik bilesimde kullanilan kaydiricilar, kalsiyum stearat, gliseril monostearat, gliseril palmitostearat, magnezyum stearat, talk, polietilen glikol, stearik asitten olusan gruptan seçilir. Tercih edilen kaydirici, talk ve magnezyum stearattir ve kapsül içerigine orani tercihen agirlikça %1-5 arasindadir. Mevcut bulus, ayrica uzun salimli tabletin enterik kaplanmasi asamasini içermektedir. Mevcut bulus, Donepezil HCl tablet kisminda, susuz laktoz, laktoz monohidrat, mikrokristalin selüloz PH 101, mikrokristalin selüloz PH 102, mikrokristalin selüloz PH 200, mikrokristalin selüloz PH 301, mikrokristalin selüloz PH 302 veya bunlarin karisimlarindan olusan bir veya iki dolgu maddesini içermektedir. Mevcut bulus, Donepezil HCl tablet kisminda, mikrokristalin selüloz PH 101, mikrokristalin selüloz PH 102, mikrokristalin selüloz PH 200, mikrokristalin selüloz PH 301, mikrokristalin selüloz PH 302 seyreltici maddelerinden birini içermektedir. Mevcut bulus, Donepezil HCl tablet kisminda, ayrica dagitici, baglayici ve/veya kaydirici maddelerini içermektedir. Mevcut bulus, Memantin HCl tabletlerin ve Donepezil HCl tabletlerin tablet baskilarinda 4 mm ila 6 mm arasinda Zimba kullanilmasi ile gerçeklestirilmistir. Bulus konusu kompozisyon oral yoldan uygulanmaktadir. Bulusun bir yapilandirmasi, Memantin HCl içeren kontrollü salim saglayan tablet ve Donepezil HCl içeren hizli salim saglayan tablet ve bu tabletlerin farkli dozlar olusturacak sekilde kapsüllenmesi ile olusan kapsül formunda farmasötik bir kompozisyon olup, özelligi; a) kontrollü salim saglayan Memantin HCl tabletlerin dört farkli dozunun bir kerede üretilmesi, b) kontrollü salim saglayan Memantin HCl tabletlerin salim kontrol ajani olarak hidroksipropil metil selüloz içermesi, c) kontrollü salim saglayan Memantin HCl tabletlerin metakrilik asit kopolimerini içeren enterik kaplama ile kaplanmasidir. Kontrollü salim saglayan tablet içerigindeki Memantin HCl miktari tercihen 7 mg, 14 mg, 21 mg veya 28 mgadir. Hizli salim saglayan tablet içerigindeki Donepezil HCl miktari tercihen 10 mgadir. Salim kontrol ajani olarak kullanilan hidroksipropil metil selülozun uzun salimli memantin HCl tablet içerigine orani tercihen agirlikça %60-80 arasindadir. Kontrollü salimli memantin HCl tabletleri tercihen direkt baski teknigi ile üretilmektedir. Hizli salimli donepezil HCl tabletleri tercihen direkt baski teknigi ile üretilmektedir. Enterik kapli uzun salimli memantin HCl tabletler ve hizli salimli donepezil HCl tabletler tercihen sert j elatin kapsül içindedir. Bulus konusu kompozisyona iliskin örnekler asagida olup, herhangi bir sekilde bulusu sinirlandirici niteligi bulunmamaktadir. Örnekler Bulus konusu kompozisyona iliskin Formül 1 (kompozisyon 1), Tablo 1, Tablo 2 ve Tablo 3lde gösterilmistir. Uzun Salimli Tablet Agirlik Orani (a/a) Memantin HC1 %l .0-%20 selüloz Mikrokristalin selüloz %5-%20 PoliVinil pirolidon % l -%5 Magnezyum Stearat %l .0-%5 .0 Metakrilik asit %3 _0-%8 _0 kopolimerlerini içeren enterik kaplama karisimi Hizli Salimli Tablet Agirlik Orani (a/a) Donepezil HC1 %5.0-%20 Laktoz %35-%50 Krospovidon % l -%5 Mikrokristalin selüloz %3 0-%50 Hidroksipropil selüloz Renklendirici ajan Magnezyum Stearat %0.5-%3.0 Memantin HC1 uzun salimli tablet 4 tablet 3 tablet 2 tablet 1 tablet Donepezil HC1 hizli salimli tablet 1 tablet 1 tablet 1 tablet 1 tablet Asagida kisa tarilî verilen prosese göre hazirlanmistir: Memantin HCl içeren uzun salimli tablet; Memantin HC1, Mikrokristalin selüloz, PoliVinil pirolidon elenir ve karistirilir. Hidroksipropil metil selüloz, elenerek eklenir ve karistirilir. Kolloidal Silikon Dioksit elenerek eklenir ve karistirilir. Talk ve Magnezyum Stearat tartilarak eklenir ve karistirilir. Karisim uygun bir kalipla tablet olarak basilir. Basilan tabletlere metakrilik asit içeren enterik kaplama karisimi ile enterik kaplama islemi uygulanir. Donepezil HCl içeren hizli salimli tablet; Donepezil HCl, laktoz, mikrokristalin selüloz ve hidroksipropil selüloz elenir ve karistirilir. Renklendirici ajan elenerek eklenir ve karistirilir. Magnezyum Stearat elenerek eklenir ve karistirilir. Karisim uygun bir kalipla tablet olarak basilir. Enterik kaplanmis Memantin HCl tabletler 28 mg, 21 mg, 14 mg veya 7 mg Memantin HCl etken maddesini içerecek miktarlarda ve hizli salimli Donepezil HCl tablet 10 mg etken maddesini içeren bir tablet seklinde kapsül içerisine doldurulur. Orijinal ürün Namzeric® 28 mg uzun salimli sert kapsüller ve mevcut bulus ile hazirlanan uzun salimli Memantin HCl tabletler ve hizli salimli Donepezil HCl tablet içeren kapsüller ile (Tablo 1, 2 ve 3,deki formülasyon) pH , 900 ml, 100 rpmade in- Vitro dissolüsyon çalismasi yapilmistir (Sekil 1 ve Sekil 2). Referans ürün ile karsilastirmali yapilan dissolüsyon grafiginden görüldügü gibi çözünme profili farmasötik olarak uygundur. Asagida ise referans ürün ile karsilastirmali biyoesdegerlik sonuçlari yer almaktadir. Biyoesdegerlik çalismasi: Ticari ürün Namzaric® 28 mg/ 10 mg mg XR Kapsül,e kiyasla tablo 1,deki kapsül içi tablet formülasyonunun biyoesdegerlik çalismasi yapilmistir. Biyoesdegerlik çalismasi açlik ve tokluk kosullarinda, 36 saglikli, yetiskin, insan gönüllülerde açik etiketli, dengeli, randomize, iki tedaVili, iki sirali, iki periyotlu, tek doz çapraz çalisma olarak gerçeklestirilmistir. Gönüllülerden alinan plazma numunelerinde donepezil ve memantin konsantrasyonlari LC MS/MS metodu ile incelenmistir. Log dönüsümlü farmakokinetik parametreler AUCO-t ve CmaX için T/R orani, %90 güven araligi olan %80.00-%125 .00 araliginda bulunmustur. Böylece, test ürün ve referans ürünün saglikli gönüllülerde, tokluk ve açlik kosullarinda biyoesdegerligi kanitlanmistir. TR TR TR TR TR TRDESCRIPTION COMPOSITION CONTAINING MEMANTININE AND DONEPEZIL Technical Field The present invention relates to the field of pharmaceutical technology and provides a capsule composition comprising a tablet containing extended-release memantine or a pharmaceutically acceptable salt thereof and a tablet containing a rapid-release donepezil or a pharmaceutically acceptable salt thereof. Prior Art Memantine HCl is an active substance known by the chemical name of 3,5-dimethyladamantan-1-amine hydrochloride and its chemical structure is as follows: H 1 : `H ,x * : h" Formula 1 Its molecular formula is C12H21N.HCl, and its molecular weight is 215.77 mg. The molecule is soluble in water. It is a BCS class 1 molecule with its high solubility and high permeability. Memantine HCl is used in the symptomatic treatment of moderate to severe Alzheimer's disease both as a monotherapy and as a cholinesterase inhibitor. It is an N-methyl-D-aspatiate (NMDA) receptor antagonist used in combination with donepezil (ChEI). It is available in the United States as 10 mg extended-release capsules. It is also available in Europe as Ebixa® (10 mg and 10 mg film-coated tablets). Donepezil HCl is an active ingredient known by the chemical name (±)-2-[(1-Benzyl-4-piperidyl)methyl]-5,6 dimethoxy-1-indanone hydrochloride and its chemical structure is as follows: Formula 2 soluble. It is a BCS class 1 molecule with high solubility and high permeability. Donepezil HCl is a reversible cholinesterase inhibitor of the piperidine type approved for the symptomatic treatment of mild to severe Alzheimer's disease. It is available in 5 mg, 10 mg and 23 mg film-coated tablets and 5 mg and 10 mg oral It is available as disintegrating tablets. The combination of donepezil and memantine, indicated for the treatment of moderate to severe Alzheimer's type dementia, is available on the market under the trade name Namzaric®. Namzaric is in the form of extended-release capsules. Rapid-release film-coated tablets containing both active ingredients are also available on the market. In the state of the art, there are different patents related to combinations of memantine and donepezil. The patent EP1509232 B1, owned by H. LUNDBECK A/S, relates to an extended-release formulation containing memantine and donepezil. A pharmaceutical composition is disclosed containing an effective amount of one or more acetylcholinesterase inhibitor(s) or their pharmaceutically effective salts and an effective amount of one or more NMDA-antagonist(s). ADAMAS PHARMACEUTICALS, INC. The patent EP1874282 B1 relates to compositions to be used in the treatment of CNS-related diseases such as Alzheimer's disease. Extended-release formulations containing memantine and Donepezil are disclosed. The patent EP1781261 A1 of Forest Laboratories, Inc. relates to an extended-release memantine formulation. An extended-release memantine tablet formulation containing a release controlling agent is disclosed. It relates to an oral dosage formulation containing memantine or an acceptable salt of memantine in combination. Corn starch and microcrystalline cellulose pH 102 were used in the intragranular phase in the formulation. The patent TR 2020/21642 of Lupin relates to extended-release formulations of Donepezil. The patent TR 2011/04108 of Ali Raif This article relates to memantine formulations consisting of two parts, one immediate-release and one immediate-release. The patents described above disclose oral pharmaceutical dosage forms containing memantine or a pharmaceutically acceptable salt of memantine and/or DonepeZil or a pharmaceutically acceptable salt of DonepeZil. However, the patents in the prior art that include both the active ingredient memantine and the active ingredient DonepeZil relate to formulations produced using the pellet technique, which is known to have very high production costs, or formulations that involve complex techniques that may increase the production cost of the drug and are difficult to apply. Therefore, there is still a need for compositions containing memantine or a pharmaceutically acceptable salt of memantine and DonepeZil or a pharmaceutically acceptable salt of DonepeZil that eliminate the problems described above in the prior art and provide additional advantages. Explanation of the figures: Figure 1. Namzaric® 28 mg/ 10 mg mg XR Capsule -Formula 1 dissolution graph-Memantine Figure 2. Namzaric® 28 mg/ 10 mg mg XR Capsule -Formula 1 dissolution graph-Donepezil Brief Description of the Invention The present invention discloses the formulation developed in the form of capsules comprising both a controlled-release tablet and an immediate-release tablet, as set forth in more detail in the following examples and claims, and the preparation method of this formulation. The present invention contains memantine or a pharmaceutically acceptable salt of memantine as the active ingredient in the controlled-release tablet portion. Preferably, it contains Memantine HCl salt. The present invention contains Donepezil or a pharmaceutically acceptable salt of donepezil in the immediate-release tablet portion. It preferably contains the dopezil HCl salt. The present invention preferably contains 7 mg, 14 mg, 21 mg, or 28 mg of Memantine HCl as a controlled-release tablet and preferably 10 mg of Donepezil HCl as an immediate-release tablet. In the present invention, capsules containing four different doses of Memantine HCl have been developed. The present invention has eliminated the production costs and waste resulting from pellet production. The finished product containing four different doses of extended-release memantine HCl can be obtained by producing a single tablet formulation. Thus, the necessity of preparing different formulations for each dose (e.g. for 7 mg, 14 mg, 21 mg or 28 mg Memantine HCl doses) is eliminated. With the present invention, the above-mentioned problems have been overcome and appropriate results have been obtained by conducting comparative bioequivalence studies with the reference product. Detailed Description of the Invention The present invention is a pharmaceutical composition in capsule form containing both a controlled-release tablet and an immediate-release tablet, and relates to a formulation containing Memantine or a pharmaceutically acceptable salt thereof as the active ingredient in the controlled-release tablet and Donepezil or a pharmaceutically acceptable salt thereof as the active ingredient in the immediate-release tablet. A pharmaceutically acceptable salt of Memantine is preferably the Hydrochloride salt. A pharmaceutically acceptable salt of Donepezil is preferably the Hydrochloride salt. The present invention relates to controlled-release pharmaceutical compositions in capsule form containing 28 mg, 21 mg, 14 mg or 7 mg Memantine HCl tablets. The present invention relates to rapid-release pharmaceutical compositions in capsule form containing 10 mg Donepezil HCl tablets. In the present invention, two different tablet compositions are prepared. One of them is extended-release, enteric-coated Memantine HCl tablets, the other is rapid-release Donepezil HCl tablets. Tablets containing memantine or a pharmaceutically acceptable salt thereof are prepared in three stages. In the first stage, core tablets containing a release controlling agent are prepared. In the second stage, the tablets are enterically coated with an enteric agent. In the third stage, the coated tablets are encapsulated. The preferred salt of memantine is the HCl salt. Tablets containing Donepezil or a pharmaceutically acceptable salt thereof are prepared in two stages. In the first stage, tablet cores are prepared. In the second stage, the tablets are encapsulated. The preferred salt of Donepezil is the HCl salt. In the present invention, the extended-release tablets containing Memantine HCl contain at least one of the release control agents, filler, diluent, binder and lubricating agent or their derivatives. In the present invention, the controlled release agent in the Memantine HCl tablet part is selected from polyethylene oxide, polyvinyl pyrrolidine, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, vinyl acetate copolymers, carbomer, polysaccharides (alginate, xanthan gum, carrageenan, etc.) or their derivatives and mixtures. More preferably, the selected polymer is hydroxypropyl methyl cellulose. The ratio of hydroxypropyl methyl cellulose used as release control agent to the content of the extended-release tablet is preferably between 40-90% by weight. More preferably between 50-70% by weight. In the present invention, the extended-release tablets in capsules contain at least one binder selected from the group consisting of carbomer, carboxymethylcellulose sodium, dextrin, dextrose, maltodextrin, gelatin, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, ethylcellulose, methylcellulose, hypromellose, polyvinyl pyrrolidone, magnesium aluminum silicate, methyl cellulose, sodium alginate, starch, pregelatinized starch, copovidone and any combination thereof. In the present invention, the extended-release tablets in capsules contain polyvinyl pyrrolidone as a binder. The ratio of polyvinyl pyrrolidone used as a binder to the extended-release tablet content is preferably between 0.5-10% by weight. More preferably, it is between 1-5% by weight. The lubricants used in the pharmaceutical composition of the present invention are selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, talc, polyethylene glycol, and stearic acid. The preferred lubricants are talc and magnesium stearate, and their ratio to the capsule content is preferably between 1-5% by weight. The present invention also includes the enteric coating step of the extended-release tablet. The present invention comprises one or two fillers consisting of anhydrous lactose, lactose monohydrate, microcrystalline cellulose PH 101, microcrystalline cellulose PH 102, microcrystalline cellulose PH 200, microcrystalline cellulose PH 301, microcrystalline cellulose PH 302 or mixtures thereof, in the Donepezil HCl tablet portion. The present invention comprises one of the diluents consisting of microcrystalline cellulose PH 101, microcrystalline cellulose PH 102, microcrystalline cellulose PH 200, microcrystalline cellulose PH 301, microcrystalline cellulose PH 302, in the Donepezil HCl tablet portion. The present invention also includes disintegrant, binder and/or lubricating agents in the Donepezil HCl tablet portion. The present invention has been carried out by using a stapler between 4 mm and 6 mm in the tablet compression of Memantine HCl tablets and Donepezil HCl tablets. The composition of the invention is administered orally. One embodiment of the invention is a pharmaceutical composition in capsule form formed by encapsulating a controlled-release tablet containing Memantine HCl and a rapid-release tablet containing Donepezil HCl and these tablets to form different doses, and is characterized by; a) producing four different doses of controlled-release Memantine HCl tablets at once, b) containing hydroxypropyl methyl cellulose as a release control agent in controlled-release Memantine HCl tablets, c) coating the controlled-release Memantine HCl tablets with an enteric coating containing methacrylic acid copolymer. The amount of Memantine HCl in the controlled-release tablet is preferably 7 mg, 14 mg, 21 mg, or 28 mg. The amount of Donepezil HCl in the immediate-release tablet is preferably 10 mg. The ratio of hydroxypropyl methyl cellulose used as a release control agent to the content of the extended-release memantine HCl tablet is preferably between 60-80% by weight. Controlled-release memantine HCl tablets are preferably produced by direct compression technique. Immediate-release Donepezil HCl tablets are preferably produced by direct compression. Enteric-coated extended-release memantine HCl tablets and immediate-release Donepezil HCl tablets are preferably in hard gelatin capsules. Examples of the compositions of the invention are provided below and are not intended to limit the invention in any way. Examples of the compositions of the invention are shown in Formula 1 (Composition 1), Table 1, Table 2, and Table 3. Extended-Release Tablet Weight Ratio (w/w) Memantine HC1 %1.0-20% cellulose Microcrystalline cellulose 5%-20% PolyVinyl pyrrolidone %1-5% Magnesium Stearate %1.0-5% .0 Methacrylic acid Enteric coating mixture containing 3% 0-8% 0 copolymers Immediate-Release Tablet Weight Ratio (w/w) Donepezil HC1 %5.0-20% Lactose 35%-50% Crospovidone %1-5% Microcrystalline cellulose 3% 0-50% Hydroxypropyl cellulose Coloring agent Magnesium Stearate 0.5-3.0% Memantine HC1 extended-release tablet 4 tablets 3 tablets 2 tablets 1 tablet Donepezil HC1 immediate-release tablet 1 tablet 1 tablet 1 tablet 1 Tablets are prepared according to the process briefly described below: Extended-release tablets containing memantine HCl; Memantine HCl, microcrystalline cellulose, and polyvinyl pyrrolidone are sieved and mixed. Hydroxypropyl methyl cellulose is sieved, added, and mixed. Colloidal silicon dioxide is sieved, added, and mixed. Talc and magnesium stearate are weighed, added, and mixed. The mixture is compressed into tablets in a suitable mold. The pressed tablets are enteric-coated with an enteric coating mixture containing methacrylic acid. Immediate-release tablets containing Donepezil HCl; Donepezil HCl, lactose, microcrystalline cellulose, and hydroxypropyl cellulose are sieved and mixed. The coloring agent is sieved, added, and mixed. Magnesium stearate is sieved, added, and mixed. The mixture is compressed into tablets in a suitable mold. Enteric-coated Memantine HCl tablets are filled into capsules in amounts containing 28 mg, 21 mg, 14 mg, or 7 mg of Memantine HCl as the active ingredient, and the immediate-release Donepezil HCl tablet is filled as a tablet containing 10 mg of the active ingredient. An in vitro dissolution study was conducted with the original product Namzeric® 28 mg extended-release hard capsules and extended-release Memantine HCl tablets prepared with the present invention and capsules containing immediate-release Donepezil HCl tablets (formulation in Tables 1, 2, and 3) at pH 900 ml and 100 rpm (Figure 1 and Figure 2). As seen in the dissolution graph compared with the reference product, the dissolution profile is pharmaceutically suitable. The bioequivalence results compared with the reference product are presented below. Bioequivalence study: A bioequivalence study was conducted for the capsule tablet formulation shown in Table 1 in comparison with the commercial product Namzaric® 28 mg/ 10 mg XR Capsule. The bioequivalence study was conducted as an open-label, balanced, randomized, two-treatment, two-sequence, two-period, single-dose crossover study in 36 healthy adult human volunteers under fasting and fed conditions. Donepezil and memantine concentrations in plasma samples from volunteers were investigated by LC MS/MS. The T/R ratio for the log-transformed pharmacokinetic parameters AUCO-t and CmaX were found to be in the range of 80.00%-125.00% with a 90% confidence interval. Thus, the bioequivalence of the test product and the reference product in healthy volunteers under fed and fasted conditions has been proven.

Claims

REQUESTS

1. It is a pharmaceutical composition in capsule form formed by encapsulating controlled release tablets containing Memantine HCl and rapid release tablets containing Donepezil HCl and these tablets in different doses, and its features are; a) four different doses of controlled release Memantine HCl tablets are produced at once, b) controlled release Memantine HCl tablets contain hydroxypropyl methyl cellulose as a release control agent, c) controlled release Memantine HCl tablets are coated with an enteric coating containing methacrylic acid copolymer.

2. A pharmaceutical composition according to claim 1, characterized in that the amount of Memantine HCl in the controlled release tablet is 7 mg, 14 mg, 21 mg or 28 mg.

3. A pharmaceutical composition according to claim 1 or 2, characterized in that the amount of Donepezil HCl in the rapid release tablet is 10 mg.

4. A pharmaceutical composition according to any of the preceding claims, characterized in that the ratio of hydroxypropyl methyl cellulose used as release control agent to the content of the sustained release memantine HCl tablet is between 60-80% by weight.

5. A pharmaceutical composition according to any of the preceding claims, characterised in that the controlled-release memantine HCl tablets are produced by direct compression technique.

6. A pharmaceutical composition according to any of the preceding claims, characterized in that the rapid release donepezil HCl tablets are produced by direct compression technique.

7. A pharmaceutical composition according to any of the preceding claims, characterized in that the enteric-coated extended-release memantine HCl tablets and the rapid-release donepezil HCl tablets are in a hard gelatin capsule.

8. A pharmaceutical composition according to any preceding claim, characterised in that it is administered orally.