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Combinations of Diacerein and Non-Steroidal Inflammation Drugs

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(19) TZZ _T (11) EP 2 797 584 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/00 (2006.01) A61K 31/00 (2006.01) 16.12.2015 Bulletin 2015/51 A61K 47/00 (2006.01) (21) Application number: 12834605.3 (86) International application number: PCT/TR2012/000247 (22) Date of filing: 25.12.2012 (87) International publication number: WO 2013/100882 (04.07.2013 Gazette 2013/27) (54) COMBINATIONS OF DIACEREIN AND NON-STEROIDAL INFLAMMATION DRUGS KOMBINATIONEN AUS DIACEREIN UND NICHTSTEROIDEN ENTZÜNDUNGSHEMMENDEN MITTELN COMBINAISONS DE DIACÉRÉINE ET D’ANTI-INFLAMMATOIRES NON STÉROÏDIENS (84) Designated Contracting States: • ZENGINER, Sibel AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 34460 Istanbul (TR) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • MUTLU, Onur PL PT RO RS SE SI SK SM TR 34460 Istanbul (TR) (30) Priority: 27.12.2011 TR 201113006 (74) Representative: Sevinç, Erkan 01.08.2012 TR 201208987 Istanbul Patent A.S. 14.12.2012 TR 201214658 Plaza-33, Büyükdere Cad. No: 33/16 Sisli (43) Date of publication of application: 34381 Istanbul (TR) 05.11.2014 Bulletin 2014/45 (56) References cited: (73) Proprietor: Sanovel Ilac Sanayi Ve Ticaret Anonim GB-A- 2 432 526 US-A- 4 996 209 Sirketi US-A1- 2004 039 366 34460 Istanbul (TR) •ÁLVAREZ-SORIA M A ET AL: "Diacerein has a (72) Inventors: weak effect on the catabolic pathway of human • CIFTER, Umit osteoarthritis synovial fibroblast", 34460 Istanbul (TR) RHEUMATOLOGY, vol. 47, no. 5, 27 March 2008 • TURKYILMAZ, Ali (2008-03-27) , pages 627-633, XP009173169, 34460 Istanbul (TR) ISSN: 1462-0324 [retrieved on 2008-03-27] • PEHLIVAN AKALIN, Nur 34460 Istanbul (TR) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 797 584 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 797 584 B1 Description Field of Invention 5 [0001] The present invention relates to novel pharmaceutical combinations with synergistic action of diacerein or a pharmaceutically acceptable salt of diacerein and non-steroidal inflammatory drugs, having analgesic, anti-inflammatory, antipyretic, and osteoarthritis-treating activities. Background of Invention 10 [0002] Diacerein, having the chemical structure given below with Formula 1, is an interleukin-1 inhibitor having an anthraquinone structure and is used for treating osteoarthritis. 15 20 25 30 [0003] Studies conducted on humans and animals have shown that diacerein alleviates the symptoms of osteoarthritis. It was further reported that diacerein reduces the osteoarthritis symptoms, particularly the pain, in a statistically significa nt manner and provides positive structural effects, when compared to placebo. The symptomatic effect of diacerein starts 30 - 45 days after the initiation of treatment. The structure modifying effect of diacerein was proposed based on the 35 findings of the ECHODIAH study, a randomized double-blind study. Diacerein is accepted as a slow-acting drug against osteoarthritis. [0004] Diacerein and more specifically rhein, which is an active metabolite thereof, is an IL-1 inhibitor. Rhein is an anthraquinone present in plants like the Cassia species and has moderate analgesic, antipyretic, and anti-inflammatory effects. It has a weak laxative effect. Diacerein inhibits human monocytes in vitro. The increase in collagenase formation 40 mediated by IL-1 in chondrocytes is actively inhibited by diacerein. Diacerein is administered orally. Following oral administration, diacerein undergoes deacetylation before it enters the systemic circulation, and is absorbed, metabolized and is excreted in the form of rhein and the conjugates thereof. [0005] Various patent applications have been filed which relate to diacerein. [0006] The patent documents US 4,244,968 and EP0636602 mention on the use of diacerein in the treatment of arthritis. 45 [0007] The document EP1248608 makes mention on the use of diacerein in the treatment of psoriazis. [0008] Non-steroidal inflammatory drugs (NSAID) have antipyretics, analgesic, anti-inflammatory activities. The main NSAID’S are flurbiprofen, loxoprofen, zaltoprofen, ibuprofen, naproxen, ketoprofen, dexketoprofen, fenoprofen, benox- aprofen, suprofen, ibuproxam, alminoprofen, dexibuprofen, indoprofen. [0009] Flurbiprofen is a propionic acid derivative, also known as NSAID (non-steroidal anti-inflammatory drug), having 50 analgesic and anti-inflammatory activities. Its chemical structure is illustrated with Formula 2 given below. 55 2 EP 2 797 584 B1 5 10 [0010] Flurbiprofen is used for alleviating pain in the muscle-skeleton system and joint disorders such as ankylosing 15 spondylitis, osteoarthritis, and rheumatoid arthritis, in soft tissue injuries such as sprains and strains, in postoperative cases, and in painful and severe menstruation and migraine. Flurbiprofen is further used as a lozenge in the symptomatic amelioration of sore throats. [0011] The document US3755427 describes the flurbiprofen molecule and the anti-inflammatory, analgesic, antipyretic and anti-toxic effects of flurbiprofen. 20 [0012] The document US4014993 discloses the use of flurbiprofen in platelet aggregation. [0013] The document EP137668 discloses the use of flurbiprofen in the treatment of alveolar bone resorption. [0014] The document EP1655026 discloses a combination of diacerein and meloxicam. [0015] No orally-administrable pharmaceutical composition has been produced until today, which contains a combi- nation of flurbiprofen and diacerein. Even if some medicaments comprising either of these active agents have been 25 administered concomitantly in practice, this fact requires the patients to carry more than one drug and causes application- related difficulties. Additionally, administering and formulating a combination, in place of the individual use of each active agent, may provide improved treatment features. [0016] In result, based on said drawbacks, a novelty is required in the art of pharmaceutical compositions having therapeutic effects against pain, inflammation, fewer, and osteoarthritis. 30 Object and Brief Description of Invention [0017] The present invention provides a composition with synergistic action of diacerein and least one agent selected from the group of non-steroidal anti-inflammatory agents consisting of flurbiprofen, loxoprofen, zaltoprofen, ibuprofen, 35 naproxen, ketoprofen, dexketoprofen, fenoprofen, benoxaprofen, suprofen, ibuproxam, alminoprofen, dexibuprofen, indoprofen, eliminating all aforesaid problems and brining additional advantages to the relevant prior art. [0018] Accordingly, the main object of the present invention is to obtain a combination composition. [0019] Another object of the present invention is to obtain a composition with synergistic action having analgesic activity. [0020] Another object of the present invention is to obtain a composition with synergistic action having artritis-treating 40 activity. [0021] Another object of the present invention is to obtain a composition with synergistic action having inflammation- treating activity. [0022] Another object of the present invention is to obtain a composition with synergistic action having antipyretic activity. 45 [0023] Another object of the present invention is to obtain a combination composition with synergistic action having therapeutic effects against inflammation, pain, fewer, and osteoarthritis. [0024] A further object of the present invention is to obtain a combination composition having content uniformity and a desired level of compatibility. [0025] In order to achieve the objects described above and to emerge in the following detailed description, a composition 50 is developed for use in the treatment of pain, inflammation, fewer, and osteoarthritis. [0026] In a preferred embodiment according to the present invention, said novelty comprises diacerein or a pharma- ceutically acceptable salt of diacerein and at least one agent selected from the group of non-steroidal anti-inflammatory agents consisting of flurbiprofen, loxoprofen, zaltoprofen, ibuprofen, naproxen, ketoprofen, dexketoprofen, fenoprofen, benoxaprofen, suprofen, ibuproxam, alminoprofen, dexibuprofen, indoprofen. 55 [0027] In another preferred embodiment according to the present invention, said non-steroidal anti-inflammatory active agent is flurbiprofen. [0028] In another preferred embodiment according to the present invention, said non-steroidal anti-inflammatory active agent is loxoprofen. 3 EP 2 797 584 B1 [0029] In another preferred embodiment according to the present invention, said non-steroidal anti-inflammatory active agent is zaltoprofen. [0030] In another preferred embodiment according to the present invention, said non-steroidal anti-inflammatory active agent is ibuprofen. 5 [0031] In another preferred embodiment according to the present invention, said non-steroidal anti-inflammatory active agent is ketoprofen or dexketoprofen. [0032] In another preferred embodiment according to the present invention, said non-steroidal anti-inflammatory active agent is naproxen. [0033] In a preferred embodiment according to the present invention, the amount of diacerein is 50 - 300 mg/day. 10 [0034] In a preferred embodiment according to the present invention,
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    DutchHatTrick: Semantic query modeling, ConText, section detection, and match score maximization. Martijn Schuemie* Dolf Trieschnigg† Edgar Meij‡ ErasmusMC University of Twente University of Amsterdam [email protected] [email protected] [email protected] Introduction This report discusses the collaborative work of the ErasmusMC, University of Twente, and the University of Amsterdam on the TREC 2011 Medical track. Here, the task is to retrieve patient visits from the University of Pittsburgh NLP Repository for 35 topics. The repository consists of 101,711 patient reports, and a patient visit was recorded in one or more reports. Because the training set provided by the track organization was small and not made available until quite late in the competition, we decided to create a small training set ourselves. Not only did this allow us to test several ideas before submitting runs to TREC, it also led to several insights into the data. One finding was that synonyms are widely used. Query expansion was therefore deemed essential to achieve a reasonable performance. Query expansion has been used before in Information Retrieval (IR), and is often divided into statistical and knowledge-based query expansion. Statistical query expansion uses data derived from the corpus itself, and a well-known example is pseudo-relevance feedback [1]. In contrast, we investigated knowledge-based query expansion, which uses a knowledge base such as an ontology or a dictionary to find related terms. This type of query expansion has not always proven to be successful. For instance, Hersh et al. [2] found a decrease in overall search performance when using the Unified Medical Language System (UMLS) [3] to find related terms.
  • Efficacy and Safety of Diacerein And

    Efficacy and Safety of Diacerein And

    2012 iMedPub Journals Vol. 1 No. 1:5 Our Site: http://www.imedpub.com/ JOURNAL OF BIOMEDICAL SCIENCES doi: 10.3823/1004 Effi cacy and safety Navin Gupta2*, Somnath Datta1 of diacerein and 1 Assistant Professor 2 Marketing Lead, Bristol Correspondence: Department of Pharmacology, Mayers Squibb, Lower Parel, diclofenac in knee FOD, Jamia Millia Islamia, Mumbai * Department of Pharmacology, New Delhi Faculty of Dentistry, Jamia osteoarthritis in Millia Islamia, New Delhi1 Indian patients- Mobile: +91-9873150172 drgargmedico2002@ a prospective yahoo.co.in randomized open Running head: Diacerein versus diclofenac effects in patients of knee osteoar- label study thritis. Keywords: Osteoarthritis, Diacerein, Diclofenac, Visual analog scale, Western On- tario and McMaster Universities Osteoarthritis Index, Lequesne impairment index What is already known about this subject: Diclofenac is a well- known NSAID used in the management of pain in Osteoarthritis(OA). Diacerein is a slow acting, disease-modifying drug approved for OA. What this study adds: Diclofenac, diacerein as well as combination of the two improved the quality of life as compared to baseline. Diacerein has acceptable toxicity and long carry-over effect in osteoarthritis patients. Abstract Objectives: To determine the effi cacy and carryover effects of diacerein vs diclof- enac in Indian population with knee osteoarthritis (OA). Study design: After one week NSAID’s washout period, patients received either diacerein or diclofenac or combination for 12 weeks with 4 weeks follow-up to determine the carryover effects of the drugs. The primary effi cacy end point was the change from baseline in 100mm visual analog scale (VAS) score after 20 meters walk.