TR201603780A1 - FORMULATIONS CONTAINING SPINGOZIN-1 PHOSPHATE RECEPTOR AGONIST - Google Patents
FORMULATIONS CONTAINING SPINGOZIN-1 PHOSPHATE RECEPTOR AGONIST Download PDFInfo
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- TR201603780A1 TR201603780A1 TR2016/03780A TR201603780A TR201603780A1 TR 201603780 A1 TR201603780 A1 TR 201603780A1 TR 2016/03780 A TR2016/03780 A TR 2016/03780A TR 201603780 A TR201603780 A TR 201603780A TR 201603780 A1 TR201603780 A1 TR 201603780A1
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- Turkey
- Prior art keywords
- oral formulation
- formulation according
- cellulose
- fingolimod
- pharmaceutically acceptable
- Prior art date
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Mevcut buluş, sfingozin-1 fosfat reseptör (S1P) agonisti ve farmasötik açıdan kabul edilebilir en az bir yardımcı madde içeren formülasyonlara, bu formülasyonların hazırlanma süreçlerine ve otoimmün sistem rahatsızlıklarında, özellikle Multipl Skleroz tedavisinde kullanımına ilişkindir. Daha spesifik olarak buluş konusu formülasyon sfingozin-1 fosfat reseptör agonisti ve farmasötik açıdan kabul edilebilir en az bir yardımcı madde içermekte olup şeker alkolü içermemektedir.The present invention relates to formulations comprising the sphingosine-1 phosphate receptor (S1P) agonist and at least one pharmaceutically acceptable excipient, processes for the preparation of such formulations and their use in the treatment of autoimmune system disorders, in particular in the treatment of Multiple Sclerosis. More specifically, the formulation of the invention comprises a sphingosine-1 phosphate receptor agonist and at least one pharmaceutically acceptable excipient, free of sugar alcohol.
Description
TARIFNAME SFINGOZIN-l FOSFAT RESEPTÖR AGONISTI IÇEREN FORMÜLASYONLAR Bulusun ilgili oldugu teknik saha Mevcut bulus, sfingozin-l fosfat reseptör (SlP) agonisti ve farrnasötik açidan kabul edilebilir en az bir yardimci madde içeren formülasyonlara, bu formülasyonlarin hazirlanma süreçlerine ve otoimmün sistem rahatsizliklarinda, özellikle Multipl Skleroz tedavisinde kullanimina iliskindir. Daha spesifik olarak bulus konusu formülasyon sfingozin-l fosfat reseptör agonisti ve farmasötik açidan kabul edilebilir en az bir yardimci madde içermekte olup seker alkolü içennemektedir. DESCRIPTION FORMULATIONS CONTAINING SFINGOZIN-l PHOSPHATE RECEPTOR AGONIST The technical field to which the invention relates The present invention is a sphingosine-1 phosphate receptor (SlP) agonist and pharmaceutically acceptable formulations containing at least one excipient, the preparation processes of these formulations and autoimmune system disorders, especially in the treatment of Multiple Sclerosis. is related. More specifically, the formulation of the invention is a sphingosine-1 phosphate receptor agonist. and at least one pharmaceutically acceptable excipient, sugar alcohol does not drink.
Teknigin bilinen durumu Multipl Skleroz (MS), etiyolojisi henüz bilinmeyen kronik bir hastalik olup, inerkezi sinir sisteminde demiyelinizasyon ve Skleroz ile karakterizedir. Demiyelinizasyon, sinir dokusunu saran özel miyelin proteinin bagisiklik sistemince yok edilmesidir. Hastalik belirgin olarak 20- 40 yas civarindaki bireylerde ortaya çikmakta ve kadinlarda daha sik görülmektedir. MS, beyin ve omuriligi etkiledigi için çok çesitli nörolojik belirtilere yol açabilir. State of the art Multiple Sclerosis (MS) is a chronic disease of unknown etiology. It is characterized by demyelination and sclerosis in the system. demyelination, nerve tissue It is the destruction of the special myelin protein that surrounds it by the immune system. The disease is markedly 20- It occurs in individuals around the age of 40 and is more common in women. MS, brain and because it affects the spinal cord, it can cause a wide variety of neurological symptoms.
MS”e bagli yakinmalar “MS atagi” sirasinda ortaya çikip daha sonra iyilesebilecegi gibi bir kismi uzun dönem kalici olabilmektedir. Her MS hastasinda ataklar sonrasindaki gelismeler zaman ve belirti olarak ayrilik gösterir. Yakinma ve belirtilerin olmadigi sessiz dönemler de (remisyon) hastalik seyrinde görülmektedir.Complaints related to MS may occur during an "MS attack" and may recover later. Some may be long-term permanent. Developments after attacks in every MS patient It differs in time and symptom. Quiet periods without complaints or symptoms (remission) is seen in the course of the disease.
Hastaligin bilinen bes düzeyi vardir: 1. Selim MS (Benign MS); hafif ataklar ve iyilesmelerin tam ya da tama yakin oldugu MS tipidir. 2. Yineleyen-Düzelen MS (Relapsing-Remitting MS); hastalik ataklar ve iyilesmelerle seyreder. Tekrarlayan ataklar sonrasinda bazi sekeller kalabilir. 3. Ikincil Ilerleyen MS (Sekonder Progresif); baslangici Relapsing-Remitting MS olup, tekararlayan ataklar sonrasi düzelme zorlasir hatta durabilir. 4. Birinci] Ilerleyen MS (Primer Progresif MS): Ataklarla birlikte ya da atak olmaksizin seyreder. Giderek artan bir ilerleme söz konusudur. 5. Ilerleyen Yineleyen MS (Progresif Relapsing MS): Baslangiçta belirgin bir atak olup tam bir düzelme olinaz. There are five known levels of the disease: 1. Selim MS (Benign MS); MS with mild attacks and complete or nearly complete recovery type. 2. Relapsing-Remitting MS; disease with attacks and recovery watches. Some sequelae may remain after recurrent attacks. 3. Secondary Progressive MS (Secondary Progressive); The onset is Relapsing-Remitting MS and after recurrent attacks recovery is difficult and may even stop. 4. First] Progressive MS (Primary Progressive MS): With Attacks It progresses with or without an attack. There is increasing progress. 5. Advancing Relapsing MS (Progressive Relapsing MS): There is a clear attack at the beginning and there is a complete recovery. olinase
MS hastaliginin kontrol altina alinmasi için çesitli tedaviler mevcuttur. lnterferon-ß ve glatireiner asetat gibi hâlihazirda mevcut olan tedavi seçenekleri orta dereceli etkinlige sahiptir, bu nedenle hastaligin ilerlemesi üzerindeki etkisi çok anlamli degildir. Ayrica mevcut tedavi seçeneklerinin sadece parenteral yol ile uygulanmasi, oral olarak uygulanacak tedavi yöntemlerine ihtiyaci arttirmaktadir. Various treatments are available to control MS. interferon-ß and Treatment options currently available, such as glatireiner acetate, have moderate efficacy, therefore, its effect on disease progression is not very significant. Also available treatment administration of options only by parenteral route, orally administered treatment increases the need for methods.
Fingolimod, oral yoldan uygulanmak üzere gelistirilmis, MS ataklarinin tekrarlanma sikligini azaltan ve hastaligin ilerlemesini geciktiren bir SlP reseptör agonistidir. F iiigolimodun aktif metaboliti olan fingolimod-fosfat, sfingozin-l fosfat reseptörlerine yüksek afinite ile baglanan bir sfingozin-l fosfat reseptör modülatörüdür. Fingolimod-fosfat, lenfositlerin lenf dügümlerinden çikma yetenegini bloke eder, böylelikle dolasimdaki lenfosit sayisini azaltir.Fingolimod, developed for oral administration, reduces the frequency of relapses of MS. It is an SlP receptor agonist that reduces and delays disease progression. F iiigolimod is active Its metabolite, fingolimod-phosphate, binds with high affinity to sphingosine-1 phosphate receptors. It is a sphingosine-1 phosphate receptor modulator. Fingolimod-phosphate, lymphocytes It blocks its ability to exit its nodes, thereby reducing the number of circulating lymphocytes.
Fingolimodun multipl sklerozda hangi mekanizmayla tedavi edici etki gösterdigi tam olarak bilinmemekle birlikte, etkinin merkezi sinir sisteinine lenfosit göçünün azalmasindan kaynaklanabilecegi düsünülmektedir. The exact mechanism by which fingolimod exerts its therapeutic effect in multiple sclerosis is not fully understood. unknown, although the effect may be due to decreased lymphocyte migration to the central nervous cysteine. is thought to be caused.
Fingolimod molekülü ve immunsupresif etkisi ilk kez EP0627406 numarali patent dokümaninda tarif edilmistir, Kimyasal adi 2-amino-2-[2-(4-0ktilfenil)etil]propan-l, 3-diol olup, kimyasal yapisi formül l”de görüldügü sekildedir. Fingolimod molecule and its immunosuppressive effect were first published in the patent number EP0627406. Chemical name 2-amino-2-[2-(4-Octylphenyl)ethyl]propane-1,3-diol and its chemical structure is as seen in formula I.
(Formül 1) Fingolimod, oral yoldan uygulandiginda hizlica absorbe olur ve mutlak biyoyararlanimi yüksektir. Fingolimodun absorpsiyon orani besin alimina bagli olarak anlamli degisiklikler göstermemektedir. (Formula 1) Fingolimod is rapidly absorbed and has absolute bioavailability when administered orally. is high. The absorption rate of fingolimod changes significantly depending on food intake. does not show.
Fingolimod içeren ticari ürün Novartis firmasi tarafindan Gilenya® ismi ile pazarlanmaktadir.The commercial product containing fingolimod is marketed by the company Novartis under the name Gilenya®.
Gilenya® isimli ticari ürün kapsül formunda olup oral yoldan uygulanmaya yöneliktir. Söz konusu ürünün oral yoldan uygulanmasi teknigin bilinen durumunda mevcut olan ve parentaral yol ile uygulanan tedavi seçeneklerine alternatif olmustur. The commercial product Gilenya® is in capsule form and is intended for oral administration. Promise Oral administration of the subject product is available in the state of the art and parenteral It has become an alternative to the treatment options applied by the road.
Fingolimod içeren kapsül formülasyonu EP1613288 numarali patent dokümaninda tarif edilmistir. Bu patent dokümaninda açiklanan kapsül formülasyonu SlP reseptör agonisti ve seker alkolü içermektedir. Seker alkolü olarak tercihen mannitol kullanilmis olup S lP reseptör agonisti içeren formülasyonlarda seker alkolü kullanmanin oral formülasyonlar için avantajli oldugu belirtilmistir. Söz konusu formülasyonun yüksek seviyede içerik tek düzeligine ve stabiliteye sahip oldugu belirtilmistir. Ayrica bu oral tedavi yöntemi teknigin bilinen duruinunda yer alan parenteral tedavi seçeneklerine kiyasla hasta kullanimi ve uyumu açisindan daha avantaj lidir.The capsule formulation containing fingolimod is described in the patent document number EP1613288. has been made. The capsule formulation described in this patent document is an SlP receptor agonist and Contains sugar alcohol. Preferably mannitol was used as sugar alcohol and S lP receptor It is advantageous for oral formulations to use sugar alcohol in formulations containing agonist. has been stated. The formulation in question has a high level of content uniformity and has been reported to be stable. In addition, this oral treatment method is known by the technique. in terms of patient use and compliance compared to parenteral treatment options in the case is more advantageous.
Bulusun çözümünü amaçladigi teknik problemler Seker alkollerinin glisemik indeksi sekerlere kiyasla daha düsüktür. Bu nedenle kan glikoz ve insülin düzeylerinde daha az degisiklige sebep olmaktadirlar. Ancak seker veya seker alkolü içermeyen bir oral formülasyon saglik açisindan daha uygun olacaktir. Teknigin bilinen durumu göz önüne alindiginda seker alkolü içermeyen bir formülasyonun gelistirilmesi hala karsilanmamis bir ihtiyaçtir. Technical problems that the invention aims to solve Sugar alcohols have a lower glycemic index than sugars. Therefore, blood glucose and cause less change in insulin levels. However, sugar or sugar alcohol An oral formulation that does not contain it would be more suitable for health. State of the art development of a sugar alcohol-free formulation is still It is an unmet need.
Bulus sahipleri gelistirmis olduklari seker alkolü içermeyeii formülasyonun Gilenya® ile benzer çözünürlük profili sergiledigini ancak stabilitesinin daha yüksek oldugunu bulmuslardir.The inventors have developed a sugar alcohol-free formulation with Gilenya®. They found that it exhibited a similar resolution profile but had higher stability.
Bulusun açiklamasi Mevcut bulus konusu formülasyon fingolimod ve farmasötik açidan kabul edilebilir en az bir yardimci madde içeren oral fonnülasyonlara yöneliktir. Description of the invention The formulation of the present invention is fingolimod and at least one pharmaceutically acceptable For oral formulations containing excipients.
Daha spesifik olarak bulus konusu formülasyon fingolimod ve farmasötik açidan kabul edilebilir en az bir yardimci madde içeren ancak seker alkolü içermeyen oral formülasyonlara yöneliktir. More specifically, the formulation of the invention is fingolimod and pharmaceutically acceptable Oral formulations containing at least one excipient but not sugar alcohol. oriented.
Bulus konusu formülasyonda kullanilan fingolimod farmasötik açidan kabul edilebilir herhangi bir tuzu, hidrati, solvati, enantiomeri, kristal formu, amorf formu veya ön-ilaci formunda olabilir. Any pharmaceutically acceptable fingolimod used in the formulation of the invention in the form of a salt, hydrate, solvate, enantiomer, crystalline form, amorphous form, or prodrug it could be.
Fingolimodun farmasötik açidan kabul edilebilir tuzu, hidroklorür, hidrobromür veya sülfat gibi inorganik asit tuzlari, asetat, fumarat, maleat, benzoat, sitrat, malat, metansülfonat veya benzensülfonat gibi organik asit tuzlari, sodyum, potasyum, kalsiyum veya alüminyum gibi metal tuzlari, trietilamin gibi amin tuzlari, lizin gibi dibazik amino asit tuzlari arasindan seçilebilir.The pharmaceutically acceptable salt of fingolimod, such as hydrochloride, hydrobromide, or sulfate salts of inorganic acids, acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or organic acid salts such as benzenesulfonate, sodium, potassium, calcium or aluminum metal salts, amine salts such as triethylamine, dibasic amino acid salts such as lysine. can be selected.
Bulus sahipleri bulus konusu formülasyonda tercihen fingolimod hidroklorür kullanmislardir. The inventors preferably used fingolimod hydrochloride in the formulation of the invention.
Bulus konusu formülasyon 0,01 - 10 mg fingolimod veya bu miktara esdeger farmasötik açidan kabul edilebilir bir tuzu, hidrati, solvati, enantiomeri, kristal formu, amorf formu veya ön-ilaci içermektedir.The formulation of the invention is 0.01 - 10 mg fingolimod or equivalent pharmaceutically to this amount. an acceptable salt, hydrate, solvate, enantiomer, crystalline form, amorphous form, or prodrug contains.
Bulus konusu formülasyonun içerdigi farmasötik açidan kabul edilebilir yardimci madde dolgu maddesi, dagitici, baglayici, lubrikaii veya bunlarin karisimi arasindan seçilebilir. Pharmaceutically acceptable excipient contained in the formulation of the invention material can be selected from dispersant, binder, lubricant or a mixture of these.
Bulus konusu formülasyonun içerdigi dolgu maddesi, selüloz, hidroksipropil selüloz, hidroksipropil metil selüloz, mikrokristalin selüloz, kalsiyum fosfat, dibazik kalsiyum fosfat, tribazik kalsiyum fosfat, kalsiyum silikat, kalsiyum karbonat, magnezyum karbonat, magnezyum oksit, kalsiyum sülfat veya bunlarin karisimi arasindan seçilebilir. The filler contained in the formulation subject to the invention is cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium silicate, calcium carbonate, magnesium carbonate, magnesium oxide, calcium sulfate or a mixture thereof.
Bulus sahipleri bulus konusu foniiülasyonda dolgu maddesi olarak tercihen mikrokristalin selüloz kullanmislardir. Inventors preferably use microcrystalline as filler in the inventive formulation. They used cellulose.
Bulus sahipleri mikrokristalin selüloz içeren fingolimod forrnülasyonlarinin stabilitesinin, mannitol içeren fingolimod formülasyonlarina kiyasla daha yüksek oldugunu bulmuslardir. The inventors determined that the stability of fingolimod formulations containing microcrystalline cellulose, found to be higher compared to fingolimod formulations containing mannitol.
Bu açidan degerlendirildiginde bulus konusu formülasyon fingolimod hidroklorür ve mikrokristalin selüloz içermekte olup mannitol veya herhangi bir seker alkolü içermemektedir. When evaluated from this point of view, the formulation of the invention is fingolimod hydrochloride and It contains microcrystalline cellulose and does not contain mannitol or any sugar alcohol.
Bulus konusu formülasyonun içerdigi dagitici, sodyum nisasta glikolat, kroskarmelloz sodyum, krospovidon, kalsiyum silikat, düsük sübstitüe hidroksipropil selüloz veya bunlarin karisimi arasindan seçilebilir. The dispersant contained in the formulation subject to the invention, sodium starch glycolate, croscarmellose sodium, crospovidone, calcium silicate, low substituted hydroxypropyl cellulose or a mixture thereof can be selected among
Bulus konusu formülasyonun içerdigi baglayici, hidroksipropil selüloz, hidroksipropil metilselüloz, metilselüloz, karboksimetilselüloz, etil selüloz, polivinilpirolidon, kopovidon, polietilen glikol, polietilen oksit, aljinik asit, sodyum al jinat, jelatin veya bunlarin karisimi arasindan seçilebilir. The binder contained in the formulation of the invention is hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, ethyl cellulose, polyvinylpyrrolidone, copovidone, polyethylene glycol, polyethylene oxide, alginic acid, sodium alginate, gelatin or a mixture thereof can be selected among
Bulus konusu forrnülasyonun içerdigi lubrikan, stearik asit, magnezyum stearat, talk, gliseril behenat, çinko stearat, hidrojene bitkisel yaglar, poliokso etilen monostearat, polietilen glikol, sodyum benzoat, sodyum lauril sülfat ve magnezyum lauril sülfat arasindan seçilebilir. Lubricant, stearic acid, magnesium stearate, talc, glyceryl contained in the formulation subject to the invention behenate, zinc stearate, hydrogenated vegetable oils, polyoxo ethylene monostearate, polyethylene glycol, sodium benzoate, sodium lauryl sulfate and magnesium lauryl sulfate.
Bulus sahipleri bulus konusu formülasyonda lubrikaii olarak tercihen olarak magnezyum stearat kullanmislardir. Inventors preferably use magnesium stearate as lubricant in the formulation of the invention. they used.
Bulus konusu forrnülasyon; - % 0,5 - % 10 araliginda fingolimod hidroklorür - % 90 - % 99 araliginda dolgu maddesi - % 0,5 - % l araliginda lubrikan içermektedir.The formulation that is the subject of the invention; - 0.5% - 10% fingolimod hydrochloride - 90% - 99% filler - Contains 0.5% - 1% lubricant.
Bulus konusu forrnülasyon spesifik olarak; - % 0,5 - % 10 araliginda fingolimod hidroklorür - % 90 - % 99 araliginda mikrokristalin selüloz - 0/0 0,5 - % l araliginda magnezyum stearat içermektedir. The formulation subject to the invention is specifically; - 0.5% - 10% fingolimod hydrochloride - Microcrystalline cellulose in the range of 90% - 99% - Contains 0/0 0.5 - % l magnesium stearate.
Bulus konusu formülasyon yas granülasyon, kuru granülasyon, kuru karistirina gibi teknigin bilinen durumunda yer alan herhangi bir üretim metodu ile üretilebilir.The formulation subject to the invention can be used in techniques such as wet granulation, dry granulation, dry mix. It can be produced by any production method in its known state.
Bulusun sanayiye uygulanma biçimi Mevcut bulus konusu formülasyon basta Multipl Skleroz (MS) olmak üzere Amiyotrofik Lateral Skleroz (ALS) ve Akut Demiyelinizan Optik Nörit (ADON) gibi Merkezi Sinir Sistemi (MSS) hastaliklarinda ve otoimmün sistem rahatsizliklarinda etkili olarak kullanilabilir. How the invention is applied to industry The formulation of the present invention is primarily Amyotrophic, especially for Multiple Sclerosis (MS). Central Nervous System such as Lateral Sclerosis (ALS) and Acute Demyelinating Optic Neuritis (ADON) It can be used effectively in CNS diseases and autoimmune system disorders.
Asagidaki örnekler bulus konusu formülasyonun daha net anlasilmasi için verilmis Olup hiçbir sekilde bulus konusunu sinirlandirmak amaçli kullanilamaz. The following examples are given for a clearer understanding of the formulation of the invention. It cannot be used to limit the subject of invention in this way.
Içerik Miktar (mg) Fingolimod hidroklorür 56 mg Magnezyum stearat 44 mg Toplam 6000 mg 56 mg fingolimod hidroklorür ve 5900 mg mikrokristalin selüloz elenir ve karistirilir. Bu karisima daha sonra 44 mg magnezyum stearat eklenir ve karistirilir. Elde edilen bu karisim kapsüllere doldurulur.Content Quantity (mg) Fingolimod hydrochloride 56 mg Magnesium stearate 44mg Total 6000mg 56 mg of fingolimod hydrochloride and 5900 mg of microcrystalline cellulose are sieved and mixed. This 44 mg of magnesium stearate is then added to the mixture and mixed. This mixture obtained filled into capsules.
Tablo 1 - Örnek 1”e uygun hazirlanan formülasyon ve Gilenya”ya ait karsilastirmali stabilite verileri (25 °C, %60 RH) Test Limitler Ürün Baslangiç 3 Ay 6 Ay Miktar Tayini % 90 - % 110 . Table 1 - Comparative stability data of the formulation prepared according to Example 1 and Gilenya (25 °C, 60% RH) Test Limits Product Initial 3 Months 6 Months Quantity Determination 90% - 110%.
Gilenya % 99.5 % 97.5 % 96.9 Safsizliklar Herhangi Bir Safsizlik maks. % 1.0 Gilenya 99.5% 97.5% 96.9% impurities Any Impurity max. 1.0%
Claims (12)
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