TR201720289A2 - Tolperizon and Selective COX-2 Inhibitor Combinations - Google Patents
Tolperizon and Selective COX-2 Inhibitor Combinations Download PDFInfo
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- TR201720289A2 TR201720289A2 TR2017/20289A TR201720289A TR201720289A2 TR 201720289 A2 TR201720289 A2 TR 201720289A2 TR 2017/20289 A TR2017/20289 A TR 2017/20289A TR 201720289 A TR201720289 A TR 201720289A TR 201720289 A2 TR201720289 A2 TR 201720289A2
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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Abstract
Mevcut buluş, tolperizon veya tolperizonun farmasötik olarak kabul edilebilir bir tuzunu, solvatını, polimorfunu, izomerini, enantiyomerini veya rasemik karışımını ve selektif COX-2 inhibitörleri veya söz konusu inhibitörlerin farmasötik olarak kabul edilebilir tuzlarını, solvatlarını, polimorflarını, izomerlerini, enantiyomerlerini veya rasemik karışımlarını içeren farmasötik kombinasyonlar ile ilgilidir.The present invention includes tolperisone or a pharmaceutically acceptable salt, solvate, polymorph, isomer, enantiomer or racemic mixture of tolperisone or tolperisone and selective COX-2 inhibitors or pharmaceutically acceptable salts, solvates, polymorphs, isomers, enantiomers or racemic mixtures of said inhibitors. It relates to pharmaceutical combinations.
Description
TARIFNAME TOLPERIZON VE SELEKTIF COX-2 INHIBITÖRÜ KOMBINASYONLARI Bulusun Alani Mevcut bulus, tolperizon veya tolperizonun farmasötik olarak kabul edilebilir bir tuzunu, solvatini, polimorfunu, izomerini, enantiyomerini veya rasemik karisimini ve selektif COX-2 inhibitörleri veya söz konusu inhibitörlerin farmasötik olarak kabul edilebilir tuzlarini, solvatlarini, polimorflarini, izomerlerini, enantiyomerlerini veya rasemik karisimlarini içeren farmasötik kombinasyonlar ile ilgilidir. DESCRIPTION TOLPERIZON AND SELECTIVE COX-2 INHIBITOR COMBINATIONS Field of Invention The present invention includes tolperisone or a pharmaceutically acceptable salt of tolperisone, solvate, polymorph, isomer, enantiomer or racemic mixture and selective COX-2 inhibitors or pharmaceutically acceptable salts of said inhibitors, Solvates, polymorphs, isomers, enantiomers or racemic mixtures relates to pharmaceutical combinations.
Teknigin Bilinen Durumu Kas gevsetici, iskelet kasi islevini etkileyen ve kas tonusunu azaltan bir ilaçtir. Kas spazmlari, agri ve hiperrefleksi gibi belirtileri hafifletmek için kullanilabilir. "Kas gevsetici" terimi, nöromüsküler blokerler ve spazmolitikler olmak üzere iki ana terapötik grubu adlandirmak için kullanilir. Nöromüsküler blokerler, nöromüsküler son plakta transmisyonu engelleyerek etki gösterirler ve santral sinir sistemine (SSS) etki etmezler. Genellikle geçici paraliz olusturmak amaciyla cerrahi prosedürlerde veya yogun bakimda ve acil servislerde kullanilirlar. Santral etkili kas gevsetici olarak da bilinen spazmolitikler, kas iskelet agrisi ve spazmlarini hafifletmek ve çesitli nörolojik kosullarda spastisiteyi azaltmak için kullanilir. Hem nöromüsküler blokerler hem de spazmolitikler siklikla kas gevsetici adi altinda gruplandirilmis olsa da, terim genellikle yalnizca spazmolitikler için kullanilir. State of the Art A muscle relaxant is a drug that affects skeletal muscle function and reduces muscle tone. muscle spasms, It can be used to relieve symptoms such as pain and hyperreflexia. The term "muscle relaxant" to name two main therapeutic groups, neuromuscular blockers and spasmolytics using for. Neuromuscular blockers inhibit transmission at the neuromuscular endplate. They have an effect and do not affect the central nervous system (CNS). Usually temporary paralysis in surgical procedures or in intensive care and emergency departments to create they are used. Spasmolytics, also known as centrally acting muscle relaxants, relieve musculoskeletal pain and It is used to relieve spasms and reduce spasticity in various neurological conditions. both Both neuromuscular blockers and spasmolytics are often referred to as muscle relaxants. Although grouped together, the term is usually used only for spasmolytics.
Tolperizon, spastisitenin ve kas spazminin semptomatik tedavisi için kullanilagelen santral etkili bir kas gevseticidir. Voltaj duyarli sodyum ve kalsiyum kanallarini bloke ederek beyin sapindaki retiküler olusumda etki gösterir ve Biocalm, Muscodol, Mydeton, Mydocalm, Mydoflex, Myolax, Myoxan ve Viveo gibi ticari isimler altinda pazarlanmaktadir. Tolperisone is the central central drug used for the symptomatic treatment of spasticity and muscle spasm. It is an effective muscle relaxant. brain by blocking voltage-sensitive sodium and calcium channels. It acts on the reticular formation in the stem and Biocalm, Muscodol, Mydeton, Mydocalm, It is marketed under trade names such as Mydoflex, Myolax, Myoxan, and Viveo.
Kimyasal adi 2-metiI-1-(4-metiIfenil)-3-piperidin-1-ilpropan-1-on olup, kimyasal yapisi Formül 1'de gösterilmektedir. Its chemical name is 2-methyl-1-(4-methylphenyl)-3-piperidin-1-ylpropan-1-one and its chemical structure is Formula It is shown in 1.
Formül 1: Tolperizon Öte yandan, non-steroidal anti-inflamatuvar ilaçlar (NSAII), ates sirasinda agriyi ve inflamasyonu azaltabilen ve vücut sicakligini düsürebilen, çok yaygin olarak reçete edilen bir ilaç türüdür. NSAII'Ier, siklooksijenaz (COX) adi verilen bir enzimi inhibe ederek çalisirlar. Bu enzim, inflamasyona neden olmak gibi birkaç farkli role sahip maddelerden birisi olan, prostaglandinler denilen kimyasallarin üretimi için gereklidir. Enzimin durulmasi ile birlikte daha az prostaglandin üretilir ve böylelikle daha az inflamasyon meydana gelir. Formula 1: Tolperisone On the other hand, non-steroidal anti-inflammatory drugs (NSAII) relieve pain and A very commonly prescribed drug that can reduce inflammation and lower body temperature. is a type of medicine. NSAIDs work by inhibiting an enzyme called cyclooxygenase (COX). This enzyme, one of the substances with several different roles such as causing inflammation, It is necessary for the production of chemicals called prostaglandins. With enzyme stagnation less prostaglandins are produced, resulting in less inflammation.
Siklooksijenaz (COX) enzimi, benzer ancak ayri etkilere sahip olan COX-1 ve COX-2 olmak üzere iki farkli formda bulunur. COX-2, inflamasyon ve atesten sorumlu enzimken, COX-1 ise gastrik mukozayi (mide astari) midenin dogal olarak ürettigi asitten korumak gibi diger islevleri yerine getirir. COX-1 ayni zamanda trombositlerin birbirine yapisarak pihti olusturmasinda rol alir. Her ikisi de böbreklere kan akisini azaltir. Çogu NSAII ile ilgili sorunlardan biri, her iki tip COX enzimini de bloke etmeleri nedeniyle bir yandan inflamasyon ve agriyi azaltirken, diger yandan mide astarinin korunmasi gibi prostaglandinlerin iyi etkilerinden bazilarini da ortadan kaldirmalariydi. Mideye yönelik koruyucu faktörlerin isleyisini etkilemeksizin sadece agri ve inflamasyondan sorumlu COX-2 enzimini hedefleyen selektif COX-2 inhibitörleri denilen NSAII'Ier de bulunmaktadir. Cyclooxygenase (COX) enzyme, being COX-1 and COX-2, which have similar but separate effects exists in two different forms. COX-2 is the enzyme responsible for inflammation and fever, while COX-1 other, such as protecting the gastric mucosa (stomach lining) from the acid naturally produced by the stomach. performs its functions. COX-1 is also the clotting of platelets by sticking to each other. takes part in its creation. Both reduce blood flow to the kidneys. One of the problems with most NSAIIs is that they block both types of COX enzymes. on the one hand, while reducing inflammation and pain, on the other hand, such as protecting the stomach lining. was that they also eliminated some of the good effects of prostaglandins. for stomach COX-2 responsible for only pain and inflammation without affecting the functioning of protective factors There are also NSAIIs called selective COX-2 inhibitors that target the enzyme.
Dolayisiyla, selektif COX-2 inhibitörlerinin, inflamatuvar hastaliklarin tedavisinde klasik non- selektif NSAII'Iere kiyasla çok daha güvenli ilaçlar olduklari söylenebilir. Therefore, selective COX-2 inhibitors can be used in the treatment of inflammatory diseases. It can be said that they are much safer drugs compared to selective NSAIDs.
Ayrica, Parkinson ve Alzheimer hastaligi gibi nörolojik hastaliklarda ve kanser kemoterapisinde selektif COX-2 inhibitörlerinin yeni kullanim yollarinin fark edilmesi, selektif COX-2 inhibitörlerinin gelistirilmesine iliskin arastirmalari çekmeye devam etmektedir. It is also used in neurological diseases such as Parkinson's and Alzheimer's disease and cancer. Recognition of new ways of using selective COX-2 inhibitors in chemotherapy, selective The development of COX-2 inhibitors continues to attract research.
Bununla birlikte, son dönemde rofekoksib gibi bazi selektif COX-2 inhibitörlerinin advers kardiyovasküler yan etkileri nedeniyle pazardan çekilmesi, arastirmacilari, COX-2 inhibitörü aktivitesiyle olusturulacak alternatif sablonlar kesfetmeye ve degerlendirmeye tesvik etmektedir. However, some selective COX-2 inhibitors, such as rofecoxib, have recently been reported to have adverse effects. withdrawal from the market due to cardiovascular side effects, researchers, COX-2 inhibitor encourage the discovery and evaluation of alternative templates to be created by the activity is doing.
Teknigin bilinen durumunda, kas gevsetici ile NSAII kombinasyonunun önerildigi az sayida patent belgesi bulunmaktadir. Örnegin WO860368 sayili patent basvurusunda, kas gevsetici ile analjezik formülasyonlarinin akut kas-iskelet problemleri olan hastalarda tek basina benzer dozlarda uygulanan analjeziklere göre daha fazla fayda sagladigi belirtilmektedir. In the state of the art, there are few cases where the combination of muscle relaxant and NSAID is recommended. has a patent certificate. For example, in the patent application numbered WO860368, muscle relaxant and analgesic formulations alone in patients with acute musculoskeletal problems It is stated that it provides more benefit than analgesics applied at similar doses.
Bununla birlikte, bu belgede NSAII türleri ve riskleri vurgulanmamakta ve farklari açiklanmamaktadir. Ancak, gastrointestinal hastalik öyküleri bulunan hastalarda non-selektif NSAII kullaniminin tehlikesi genel bilgi dahilindedir. However, this document does not highlight the types and risks of NSAII and their differences. is not disclosed. However, it is non-selective in patients with a history of gastrointestinal disease. The danger of NSAII use is within the general knowledge.
Tolperizonun NSAII veya NSAII olmayan bir etkin madde ile olan spesifik kombinasyonlari da önceki teknikte mevcuttur. Örnegin, EP161078581 sayili patent belgesinde tolperizon ile dekstrometorfanin spastisite ve agri tedavisindeki kombine etkisi ortaya konulmaktadir. Specific combinations of tolperisone with an NSAII or a non-NSAII active substance may also be used. available in the prior art. For example, with tolperisone in patent document EP161078581 The combined effect of dextromethorphan in the treatment of spasticity and pain is demonstrated.
EP167778781 sayili bir baska patent belgesinde, kas tonusunda artis ile seyreden agrinin tedavisinde tolperizon ve flupirtin kombinasyonu önerilmektedir. In another patent document numbered EP16777878, it is stated that pain progressing with an increase in muscle tone A combination of tolperisone and flupirtine is recommended for treatment.
Teknigin bilinen durumu göz önüne alindiginda halen spazmodik ve artritik bozukluklar üzerindeki terapötik etkiyi arttiran ve ayni zamanda gastrointestinal ve kardiyovasküler güvenlik ve hasta uyuncu saglayan, tolperizon ile kombinasyon halinde bir selektif COX-2 inhibitörü içeren bir dozaj formuna ihtiyaç duyulmaktadir. Considering the state of the art, spasmodic and arthritic disorders still exist. enhancing the therapeutic effect on and at the same time gastrointestinal and cardiovascular a selective COX-2 in combination with tolperisone, providing safety and patient compliance. There is a need for a dosage form containing the inhibitor.
Bulusun Amaçlari ve Kisa Açiklamasi Mevcut bulusun esas amaci, tolperizon veya tolperizonun farmasötik olarak kabul edilebilir bir tuzunu, solvatini, polimorfunu, izomerini, enantiyomerini veya rasemik karisimini ve selektif COX-2 inhibitörleri veya söz konusu inhibitörlerin farmasötik olarak kabul edilebilir tuzlarini, solvatlarini, polimorflarini, izomerlerini, enantiyomerlerini veya rasemik karisimlarini içeren ve yukarida belirtilen tüm problemleri ortadan kaldirarak önceki teknige ek avantajlar getiren kombinasyonlar elde edilmesidir. Objectives and Brief Description of the Invention The main object of the present invention is that tolperisone or tolperisone is pharmaceutically acceptable. a salt, solvate, polymorph, isomer, enantiomer or racemic mixture; and selective COX-2 inhibitors or such inhibitors are pharmaceutically acceptable salts, solvates, polymorphs, isomers, enantiomers or racemic mixtures Additional advantages over the prior art by eliminating all the above-mentioned problems involving obtaining combinations.
Mevcut bulusun bir baska amaci, tolperizon ile selektif COX-2 inhibitörlerinin kardiyovasküler ve gastrointestinal güvenlik ve hasta uyuncu saglayan kompozisyonlarinin elde edilmesidir. Another object of the present invention is the cardiovascular effects of tolperisone and selective COX-2 inhibitors. and obtaining compositions that provide gastrointestinal safety and patient compliance.
Mevcut bulusun bir baska amaci, tolperizon ile selektif COX-2 inhibitörlerinin yüksek stabilite ve biyoyararlanim sunan kompozisyonlarinin gelistirilmesidir. Another object of the present invention is the high stability of selective COX-2 inhibitors with tolperisone. and the development of compositions offering bioavailability.
Mevcut bulusun bir baska amaci, tolperizon ile selektif COX-2 inhibitörlerinin daha yüksek çözünme hizi ve çözünürlük düzeyine sahip kompozisyonlarinin gelistirilmesidir. Another object of the present invention is to increase the selective COX-2 inhibitors with tolperisone. is to develop compositions with dissolution rate and solubility level.
Mevcut bulusun bir baska amaci, spazmodik ve artrit bozukluklarin tedavisi ve önlenmesinde kullanilmak üzere tolperizon ve bir selektif COX-2 inhibitörü içeren bir tablet dozaj formunun saglanmasidir. Another object of the present invention is the treatment and prevention of spasmodic and arthritis disorders. a tablet dosage form containing tolperisone and a selective COX-2 inhibitor for use. is to provide.
Bulusun Ayrintili Açiklamasi Yukarida belirtilen amaçlara uygun olarak, mevcut bulusun ayrintili özellikleri burada verilmektedir. Detailed Description of the Invention For the above-mentioned purposes, detailed features of the present invention are herein are given.
Mevcut bulus, tolperizon veya tolperizonun farmasötik olarak kabul edilebilir bir tuzu, solvati, polimorfu, izomeri, enantiyomeri veya rasemik karisimi ile kombinasyon halinde bir selektif COX-2 inhibitörünü veya söz konusu inhibitörün farmasötik olarak kabul edilebilir bir tuzunu, solvatini, polimorfunu, izomerini, enantiyomerini veya rasemik karisimini içeren farmasötik kompozisyonlarla ilgilidir. The present invention is tolperisone or a pharmaceutically acceptable salt of tolperisone, solvati, a selective in combination with a polymorph, isomer, enantiomer or a racemic mixture. COX-2 inhibitor or a pharmaceutically acceptable salt of said inhibitor, pharmaceutical containing solvate, polymorph, isomer, enantiomer or racemic mixture It's about compositions.
Bulusun tercih edilen uygulamasina göre söz konusu selektif COX-2 inhibitörü; nimesulid, etorikoksib, Iumirakoksib, meloksikam, parekoksib, parekoksib sodyum, selekoksib veya valdekoksib veya bunlarin karisimlarini içeren gruptan seçilmektedir. According to the preferred embodiment of the invention, said selective COX-2 inhibitor; nimesulide, etoricoxib, Iumiracoxib, meloxicam, parecoxib, parecoxib sodium, celecoxib, or valdecoxib or mixtures thereof.
Bulusun tercih edilen uygulamasina göre söz konusu selektif COX-2 inhibitörü nimesuliddir. According to a preferred embodiment of the invention, said selective COX-2 inhibitor is nimesulide.
En çok tercih edilen uygulamada, oral farmasötik kompozisyon, kombine edilmis aktif ajanlar olarak tolperizon ve nimesulid içermektedir. In the most preferred embodiment, the oral pharmaceutical composition is combined with active agents. It contains tolperisone and nimesulide.
Tercih edilen bir uygulamaya göre tolperizon miktari, toplam kompozisyonun agirliginca %1- 50 arasindadir. Tercihen bu miktar, toplam kompozisyonun agirliginca %5-40 arasindadir. According to a preferred embodiment, the amount of tolperisone is 1%- by weight of the total composition. It is between 50. Preferably, this amount is between 5-40% by weight of the total composition.
Daha tercihen tolperizon, toplam kompozisyonun agirliginca %15-35 arasinda bulunmaktadir. More preferably, tolperisone is between 15-35% by weight of the total composition. are available.
Bulusun tercih edilen uygulamasinda, nimesulidin tolperizona agirlikça orani, 120.025 ila 1:50 121.5'tir. In the preferred embodiment of the invention, the weight ratio of nimesulide to tolperisone is from 120.025 to 1:50. It is 121.5.
Tercih edilen bir uygulamaya göre nimesulid miktari, toplam kompozisyonun agirliginca %1- 40 arasindadir. Tercihen bu miktar, toplam kompozisyonun agirliginca %5-30 arasindadir. According to a preferred embodiment, the amount of nimesulide is 1% by weight of the total composition. It is between 40. Preferably, this amount is between 5-30% by weight of the total composition.
Daha tercihen nimesulid, toplam kompozisyonun agirliginca %10-20 arasinda bulunmaktadir. More preferably, nimesulide is in the range of 10-20% by weight of the total composition. are available.
Bir uygulamaya göre tolperizon, toplam kompozisyonda 1 ila 500 mg, daha tercihen 5 ila 250 mg miktarinda mevcuttur. According to one embodiment, tolperisone is 1 to 500 mg, more preferably 5 to 250 mg in total composition. Available in mg.
Bu uygulamaya göre nimesulid, toplam kompozisyonda 1 ila 300 mg, daha tercihen 50 ila 150 mg miktarinda mevcuttur. According to this embodiment, nimesulide is 1 to 300 mg, more preferably 50 to 300 mg in total composition. It is available in the amount of 150 mg.
Bulusun tercih edilen uygulamasina göre kompozisyon, seyrelticiler, dagiticilar, baglayicilar, farmasötik olarak kabul edilebilir eksipiyan içermektedir. According to the preferred embodiment of the invention, the composition includes diluents, dispersants, binders, Contains pharmaceutically acceptable excipient.
Bulusun bir uygulamasina göre oral farmasötik kompozisyon; Iaktoz monohidrat, mikrokristalin selüloz, Iaktoz, dibazik kalsiyum fosfat, manitol, spreyle kurutulmus manitol, dekstroz, sukroz, fruktoz, maltoz, sorbitol, ksilitol, inositol, kaolin, inorganik tuzlar, kalsiyum tuzlari, polisakkaritler, dikalsiyum fosfat, sodyum klorür, dekstratlar, Iaktitol, maltodekstrin, sukroz-maltodekstrin karisimi, trehaloz, sodyum karbonat, sodyum bikarbonat, kalsiyum karbonat veya bunlarin karisimlarini içeren gruptan seçilen en az bir seyreltici içermektedir. Oral pharmaceutical composition according to one embodiment of the invention; lactose monohydrate, microcrystalline cellulose, lactose, dibasic calcium phosphate, mannitol, spray-dried mannitol, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, Iactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof, at least one diluent selected from the group consisting of.
Bulusun tercih edilen uygulamasina göre oral farmasötik kompozisyon; Iaktoz monohidrat, mikrokristalin selüloz ve Iaktoz olmak üzere üç seyreltici içermektedir. The oral pharmaceutical composition according to the preferred embodiment of the invention; lactose monohydrate, It contains three diluents, microcrystalline cellulose and Iactose.
Laktoz monohidrat miktari, toplam kompozisyonda agirlikça %1-50, tercihen %5-30, daha tercihen %10-20 arasindadir. The amount of lactose monohydrate is 1-50%, preferably 5-30%, by weight in the total composition, more preferably between 10-20%.
Mikrokristalin selüloz miktari, toplam kompozisyonda agirlikça %1-50, tercihen %5-30, daha tercihen %10-20 arasindadir. The amount of microcrystalline cellulose is 1-50%, preferably 5-30%, by weight in the total composition, more preferably between 10-20%.
Laktoz miktari, toplam kompozisyonda agirlikça %1-50, tercihen %5-30, daha tercihen %10- arasindadir. The amount of lactose is 1-50%, preferably 5-30%, more preferably 10%- by weight of the total composition. are in between.
Bulusun bir uygulamasina göre oral farmasötik kompozisyon; sodyum nisasta glikolat, kroskarmelloz sodyum, sodyum karbonat, hidroksipropil selüloz (HPC), çapraz bagli polivinilpirolidon (krospovidon), kopovidon, polikarbofil, düsük sübstitüye poloksamer, aljinik asit ve aljinatlar, iyon degistirici reçineler, magnezyum alüminyum silika, sodyum dodesil sülfat, sodyum karboksi metil selüloz, karboksi metil selüloz kalsiyum, dokusat sodyum, guar zamki, poliakrilin potasyum, sodyum aljinat, sodyum glisin karbonat, sodyum lauril sülfat veya bunlarin karisimlarini içeren gruptan seçilen en az bir dagitici içermektedir. Oral pharmaceutical composition according to one embodiment of the invention; sodium starch glycolate, croscarmellose sodium, sodium carbonate, hydroxypropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidone), copovidone, polycarbophil, low substituted poloxamer, alginic acids and alginates, ion exchange resins, magnesium aluminum silica, sodium dodecyl sulfate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, docusate sodium, guar gum, polyacryline potassium, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate or mixtures thereof, at least one dispersant selected from the group consisting of.
Bulusun tercih edilen uygulamasina göre oral farmasötik kompozisyon, sodyum nisasta glikolat olmak üzere bir dagitici içermektedir. Sodyum nisasta glikolat miktari, toplam kompozisyonun agirliginca %1-30, tercihen %5-15 arasindadir. The oral pharmaceutical composition according to the preferred embodiment of the invention is sodium starch It contains a dispersant, glycolate. Amount of sodium starch glycolate, total 1-30%, preferably 5-15%, by weight of the composition.
Bir uygulamaya göre oral farmasötik kompozisyon; hidroksipropil selüloz (HPC), kopovidon, kopolipidon, polivinilpirolidon (PVP), povidon K30, karnauba mumu, hidroksipropil metil selüloz (hipromelloz, HPMC), pullulan, polimetakrilat, gliseril behenat, karboksimetil selüloz (CMC), hidroksietil selüloz, sodyum karboksimetil selüloz (Na CMC), etil selüloz, mikrokristalin selüloz, polimetakrilatlar, polietilen oksit, polivinil alkol, polikarbofil, polivinil asetat ve kopolimerleri, jelatin, ksantan zamki, guar zamki, aljinat, karragen, kollagen, agar, pektin, hiyalüronik asit, karbomer, selüloz asetat ftalat, hidroksietil metil selüloz, polaksomer, polietilen glikol (PEG), sekerler, glikoz suruplari, dogal zamklar, tragasant zamki, poliakrilamid, alüminyum hidroksit, bentonit, Iaponit, setostearil alkol, polioksietilen-alkil eterler, akasya müsilaji, polidekstroz veya bunlarin karisimlarini içeren gruptan seçilen en az bir baglayici içermektedir. Oral pharmaceutical composition according to one embodiment; hydroxypropyl cellulose (HPC), copovidone, copolipidone, polyvinylpyrrolidone (PVP), povidone K30, carnauba wax, hydroxypropyl methyl cellulose (hypromellose, HPMC), pullulan, polymethacrylate, glyceryl behenate, carboxymethyl cellulose (CMC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), ethyl cellulose, microcrystalline cellulose, polymethacrylates, polyethylene oxide, polyvinyl alcohol, polycarbophil, polyvinyl acetate and its copolymers, gelatin, xanthan gum, guar gum, alginate, carrageenan, collagen, agar, pectin, hyaluronic acid, carbomer, cellulose acetate phthalate, hydroxyethyl methyl cellulose, polaxomer, polyethylene glycol (PEG), sugars, glucose syrups, natural gums, tragasant gum, polyacrylamide, aluminum hydroxide, bentonite, Iaponit, cetostearyl alcohol, polyoxyethylene-alkyl at least one selected from the group consisting of ethers, acacia mucilage, polydextrose or mixtures thereof. includes a binder.
Bulusun tercih edilen uygulamasina göre oral farmasötik kompozisyon, hidroksipropil selüloz (HPC) olmak üzere bir baglayici içermektedir. HPC miktari, toplam kompozisyonun agirliginca %0.01-5, tercihen %0.05-0.5 arasindadir. The oral pharmaceutical composition according to the preferred embodiment of the invention is hydroxypropyl cellulose. It contains a binder (HPC). HPC amount, total composition It is between 0.01-5%, preferably 0.05-0.5% by weight.
Bir uygulamaya göre oral farmasötik kompozisyon; susuz sitrik asit, alkali metal sitrat, sitrik asit/sodyum sitrat, tartarik asit, fumarik asit, sorbik asit, sitrik asit, süksinik asit, adipik asit, askorbik asit, glutarik asit, potasyum hidrojen tartrat, sodyum hidrojen tartrat, potasyum hidrojen ftalat, sodyum hidrojen ftalat, potasyum dihidrojen fosfat, sodyum dihidrojen fosfat, disodyum hidrojen fosfat, hidroklorik asit/sodyum hidroksit veya bunlarin karisimlarini içeren gruptan seçilen bir tamponlama ajani içermektedir. Oral pharmaceutical composition according to one embodiment; anhydrous citric acid, alkali metal citrate, citric acid/sodium citrate, tartaric acid, fumaric acid, sorbic acid, citric acid, succinic acid, adipic acid, ascorbic acid, glutaric acid, potassium hydrogen tartrate, sodium hydrogen tartrate, potassium hydrogen phthalate, sodium hydrogen phthalate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, containing disodium hydrogen phosphate, hydrochloric acid/sodium hydroxide or mixtures thereof contains a buffering agent selected from the group
Bulusun tercih edilen uygulamasina göre oral farmasötik kompozisyon, susuz sitrik asit olmak üzere bir tamponlama ajani içermektedir. Susuz sitrik asit miktari, toplam kompozisyonun agirliginca %O.5-10, tercihen %1-5 arasindadir. According to the preferred embodiment of the invention, the oral pharmaceutical composition is anhydrous citric acid. Contains a buffering agent. Amount of anhydrous citric acid, total 0.5-10%, preferably 1-5% by weight of the composition.
Bir uygulamaya göre oral farmasötik kompozisyon; sodyum stearil fumarat, kolloidal silikon dioksit, sodyum Iauril sülfat, magnezyum stearat, çinko stearat, kalsiyum stearat, mineral yag, talk, polietilen glikol, gliseril monostearat, gliseril palmitostearat, magnezyum Iauril sülfat, fumarik asit, çinko stearat, stearik asit, hidrojene dogal yaglar, silika, parafin veya bunlarin karisimlarini içeren gruptan seçilen en az bir Iubrikant ve bir glidant içermektedir. Oral pharmaceutical composition according to one embodiment; sodium stearyl fumarate, colloidal silicon dioxide, sodium lauryl sulfate, magnesium stearate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium Iauril sulfate, fumaric acid, zinc stearate, stearic acid, hydrogenated oils, silica, paraffin or at least one lubricant and one glidant selected from the group consisting of mixtures thereof.
Bulusun tercih edilen uygulamasina göre kati oral farmasötik kompozisyon, sodyum stearil fumarat ve talk olmak üzere iki Iubrikant içermektedir. The solid oral pharmaceutical composition according to the preferred embodiment of the invention is sodium stearyl. It contains two lubricants, fumarate and talc.
Sodyum stearil fumarat miktari, toplam kompozisyonun agirliginca %0.1-10, tercihen %1-5 arasindadir. The amount of sodium stearyl fumarate is 0.1-10% by weight of the total composition, preferably 1-5% are in between.
Talk miktari, toplam kompozisyonun agirliginca %0.05-5, tercihen %0.1-1 arasindadir. The amount of talc is between 0.05-5%, preferably 0.1-1%, by weight of the total composition.
Bulusun tercih edilen uygulamasina göre kati oral farmasötik kompozisyon, kolloidal silikon dioksit olmak üzere bir glidant içermektedir. The solid oral pharmaceutical composition according to the preferred embodiment of the invention is colloidal silicone. It contains a glidant, namely dioxide.
Kolloidal silikon dioksit miktari, toplam kompozisyonun agirliginca %0.05-5, tercihen %0.1-1 arasindadir. The amount of colloidal silicon dioxide is 0.05-5%, preferably 0.1-1%, by weight of the total composition. are in between.
Bu uygulamalara göre kompozisyon; tablet, kapli tablet, film kapli tablet, üç katmanli tablet, iki katmanli tablet, çok katmanli tablet, agizda dagilan tablet, mini tablet, iç içe tablet, inlay tablet, bukkal tablet, dil alti tablet, efervesan tablet, çabuk salim saglayan tablet, modifiye salim saglayan tablet, midede dagilan tablet, pellet, seker pelleti, hap, kapsül, oral granül, toz, kapli boncuk sistemi, mikroküre, draje, sase veya oral uygulanabilir film formundadir. Composition according to these applications; tablet, coated tablet, film-coated tablet, tri-layer tablet, bi-layer tablet, multi-layer tablet, mouth dispersing tablet, mini tablet, nested tablet, inlay tablet, buccal tablet, sublingual tablet, effervescent tablet, immediate release tablet, modified releasing tablet, stomach dispersing tablet, pellet, sugar pellet, pill, capsule, oral granule, powder, coated bead system, microsphere, dragee, sachet or orally applicable film.
Kompozisyon; tercihen tablet, kapli tablet, film kapli tablet formunda; en tercih edilen haliyle Bulusun bir uygulamasina göre kati oral farmasötik kompozisyon; kompozisyonu neme karsi korumak ve stabilitenin devamliligini saglamak için en az bir kaplama katmani içermektedir. Composition; preferably in the form of tablets, coated tablets, film-coated tablets; most preferred Solid oral pharmaceutical composition according to one embodiment of the invention; composition against moisture It contains at least one coating layer to protect and maintain stability.
Uygun kaplama maddeleri, hidroksipropilmetil selüloz (hipromelloz), Iaktoz monohidrat, hidroksipropil selüloz, polivinil alkol (PVA), polietilen glikol (PEG), talk, polivinil alkol-polietilen glikol kopolimerleri (Kollicoat IR), etilselüloz dispersiyonlari (Surelease), polivinilprolidon, polivinilprolidon-vinil asetat kopolimeri (PVP-VA) ve her türlü OpadryT'V' pigmenti, boyalar, titanyum dioksit, demir oksit veya polimetilmetakrilat kopolimerleri veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable coating agents are hydroxypropylmethyl cellulose (hypromellose), Iactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat IR), ethylcellulose dispersions (Surelease), polyvinylprolidon, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA) and all kinds of OpadryT'V' pigments, dyes, copolymers of titanium dioxide, iron oxide or polymethylmethacrylate, or mixtures thereof selected from the group containing
Bir uygulamaya göre kaplama katmani, hidroksipropilmetil selüloz (hipromelloz), hidroksipropil selüloz, titanyum dioksit, kuinolin sari boya (D & C sari n0.10) içeren Opadry II Bu uygulamalara göre kompozisyon asagidakileri içermektedir: - Agirlikça %1-50 mikrokristalin selüloz, - Agirlikça %1-50 laktoz - Agirlikça %1-30 sodyum nisasta glikolat, - Agirlikça %0.01-5 hidroksipropil selüloz, - Agirlikça %0.5-10 susuz sitrik asit, - Agirlikça %0.1-10 sodyum stearil fumarat, - Agirlikça %0.05-5 kolloidal silikon dioksit, - Agirlikça %1-5 kaplama, Analitik olarak seçilen bu oranlar, tedavi için gereken etkili dozlari, kardiyovasküler ve gastrointestinal güvenligi ve hasta uyuncunu saglamaktadir. Ek olarak, bulusun konusu olan film kapli tabletin stabilitesini, biyoyararlanimini ve çözünme profilini arttirir. According to one embodiment, the coating layer is hydroxypropylmethyl cellulose (hypromellose), Opadry II with hydroxypropyl cellulose, titanium dioxide, quinoline yellow dye (D&C yellow n0.10) According to these applications, the composition includes: - 1-50% microcrystalline cellulose by weight, - 1-50% lactose by weight - 1-30% sodium starch glycolate by weight, - 0.01-5% by weight of hydroxypropyl cellulose, - 0.5-10% by weight anhydrous citric acid, - 0.1-10% by weight sodium stearyl fumarate, - 0.05-5% colloidal silicon dioxide by weight, - 1-5% coating by weight, These analytically selected ratios determine the effective doses required for treatment, cardiovascular and It provides gastrointestinal safety and patient compliance. In addition, the subject of the invention It increases the stability, bioavailability and dissolution profile of the film-coated tablet.
Tüm bu uygulamalara göre, asagida belirtilen formülasyonlar, bulusun konusu olan kati oral farmasötik kompozisyonda kullanilabilir. Bu örnekler mevcut bulusun kapsamini sinirlamaz ve yukarida belirtilen ayrintili açiklamanin isigi altinda degerlendirilmelidir. Örnek 1: Film kapli tablet formülasyonu Içerik maddeleri Miktar (%) Tolperizon 1 - 50 Nimesulid 1 - 40 Laktoz monohidrat 1 - 50 Mikrokristalin selüloz 1 - 50 Laktoz 1 - 50 Hidroksipropil selüloz 0.01 - 5 Susuz sitrik asit 0.5 - 10 Sodyum stearil fumarat 0.1 - 10 Kolloidal silikon dioksit 0.05 - 5 Kaplama Malzemesi (Opadry ll sari) Içerik Maddeleri Miktar (%) Hipromelloz (Methocel E5 LV) 30 - 50 Titanyum dioksit 10 - 30 Sari boya (D&C sari no.10) 1 - 3 Örnek 2: Film kapli tablet formülasyonu Içerik maddeleri Miktar (%) Tolperizon 25.00 Nimesulid 16.68 Laktoz monohidrat 13.33 Mikrokristalin selüloz 16.67 Laktoz 12.50 Sodyum nisasta glikolat 8.83 Hidroksipropil selüloz 0.13 Susuz sitrik asit 3.33 Sodyum stearil fumarat 2.50 Total tablet 100 Kapli tablet 103 Bulusun konusu olan, yukarida belirtilmis 1. ve 2. Örnekteki film kapli tablet formu hazirlama yöntemi su adimlardan olusmaktadir: Nimesulid, Iaktoz monohidrat, mikrokristalin selüloz ve sodyum nisasta glikolatin agirlikça %60-70'inin karistirilmasi Karisimin, akiskan yatakli kurutucuya beslenmesi Karisimin, agirlikça %0.45 (a/a) sulu hidroksipropil selüloz çözeltisi ile sprey granülasyon islemine tabi tutulmasi Granüllerin kurutulmasi Tolperizon, Iaktoz, sodyum nisasta glikolatin agirlikça %30-40'i ve kolloidal silikon dioksitin karistirilmasi ve bu karisimin elenmesi Granüllerin bu karisima eklenmesi ve beraberce karistirilmasi Sirasiyla talk ve sodyum stearil fumaratin eklenmesi ve son karisimin karistirilmasi Son karisimin tabletlere basilmasi Kaplama malzemesinin sulu karisiminin hazirlanmasi ve tabletlerin bu çözelti ile kaplanarak birfilm katmaninin olusturulmasi According to all these applications, the following formulations are the solid oral formulations of the invention. can be used in pharmaceutical composition. These examples do not limit the scope of the present invention. and should be evaluated in the light of the above detailed explanation. Example 1: Film-coated tablet formulation Ingredients Quantity (%) Tolperisone 1 - 50 Nimesulide 1 - 40 Lactose monohydrate 1 - 50 Microcrystalline cellulose 1 - 50 Lactose 1 - 50 Hydroxypropyl cellulose 0.01 - 5 Anhydrous citric acid 0.5 - 10 Sodium stearyl fumarate 0.1 - 10 Colloidal silicon dioxide 0.05 - 5 Covering Material (Opadry ll yellow) items Quantity (%) Hypromellose (Methocel E5 LV) 30 - 50 Titanium dioxide 10 - 30 Yellow paint (D&C yellow no.10) 1 - 3 Example 2: Film-coated tablet formulation Ingredients Quantity (%) Tolperisone 25.00 Nimesulide 16.68 Lactose monohydrate 13.33 Microcrystalline cellulose 16.67 Lactose 12.50 Sodium starch glycolate 8.83 Hydroxypropyl cellulose 0.13 Anhydrous citric acid 3.33 Sodium stearyl fumarate 2.50 Total tablets 100 coated tablet 103 Preparation of the film-coated tablet form in the 1st and 2nd Examples mentioned above, which is the subject of the invention method consists of the following steps: Nimesulide, Iactose monohydrate, microcrystalline cellulose and sodium starch glycolatine mixing 60-70% by weight Feeding the mixture to the fluidized bed dryer Spray the mixture with 0.45% (w/w) aqueous solution of hydroxypropyl cellulose granulation process Drying of granules Tolperisone, Iactose, sodium starch 30-40% by weight of glycolate and colloidal silicon mixing the dioxide and sieving this mixture Adding the granules to this mixture and mixing them together Adding talc and sodium stearyl fumarate, respectively, and mixing the final mixture. Pressing the final mix into tablets Preparation of the aqueous mixture of the coating material and the preparation of the tablets with this solution. forming a film layer by coating
Claims (24)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2017/20289A TR201720289A2 (en) | 2017-12-13 | 2017-12-13 | Tolperizon and Selective COX-2 Inhibitor Combinations |
| PCT/TR2018/050798 WO2019203751A2 (en) | 2017-12-13 | 2018-12-12 | Tolperisone and selective cox-2 inhibitor combinations |
| EP18915012.1A EP3723736A4 (en) | 2017-12-13 | 2018-12-12 | Tolperisone and selective cox-2 inhibitor combinations |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2017/20289A TR201720289A2 (en) | 2017-12-13 | 2017-12-13 | Tolperizon and Selective COX-2 Inhibitor Combinations |
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| Publication Number | Publication Date |
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| TR201720289A2 true TR201720289A2 (en) | 2019-06-21 |
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| TR2017/20289A TR201720289A2 (en) | 2017-12-13 | 2017-12-13 | Tolperizon and Selective COX-2 Inhibitor Combinations |
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| EP (1) | EP3723736A4 (en) |
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| TR201906487A1 (en) * | 2019-04-30 | 2020-11-23 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | PHARMACEUTICAL COMPOSITIONS CONTAINING TOLPERISONE AND NIMESULIDE COMBINATIONS |
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| US20040204413A1 (en) * | 2001-01-26 | 2004-10-14 | Joaquina Faour | Pharmaceutical compositions containing a COX-II inhibitor and a muscle relaxant |
| HUP0300929A3 (en) * | 2003-04-09 | 2005-06-28 | Richter Gedeon Vegyeszet | Analgetic and/or muscle relaxant pharmaceutical composition |
| WO2010103544A2 (en) * | 2009-03-09 | 2010-09-16 | Dinesh Shantilal Patel | A novel sustained release composition of compounds selected from the class of centrally acting muscle relaxants |
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| Publication number | Publication date |
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| EP3723736A2 (en) | 2020-10-21 |
| WO2019203751A3 (en) | 2019-11-28 |
| EP3723736A4 (en) | 2021-07-14 |
| WO2019203751A2 (en) | 2019-10-24 |
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