Water Soluble Curcumin Compositions for Use in Anti

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Water Soluble Curcumin Compositions for Use in Anti (19) TZZ ¥Z¥¥ _T (11) EP 2 303 328 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 45/06 (2006.01) A61K 31/724 (2006.01) 20.12.2017 Bulletin 2017/51 A61P 35/00 (2006.01) (21) Application number: 09753875.5 (86) International application number: PCT/EP2009/056369 (22) Date of filing: 26.05.2009 (87) International publication number: WO 2009/144220 (03.12.2009 Gazette 2009/49) (54) WATER SOLUBLE CURCUMIN COMPOSITIONS FOR USE IN ANTI-CANCER AND ANTI-INFLAMMATORY THERAPY LÖSLICHE KURKUMINZUSAMMENSETZUNGEN ZUR BEHANDLUNG VON KREBS UND ENTZÜNDUNGSERKRANKUNGEN COMPOSITIONS DE CURCUMA SOLUBLES POUR UNE UTILISATION DANS UNE THÉRAPIE CONTRE LE CANCER ET ANTI-INFLAMMATOIRE (84) Designated Contracting States: • ROCKS, Natacha AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 4720 La Calamine (BE) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK TR (74) Representative: Vanhalst, Koen et al De Clercq & Partners cvba (30) Priority: 29.05.2008 EP 08157160 E. Gevaertdreef 10a 29.05.2008 US 57078 P 9830 Sint-Martens-Latem (BE) (43) Date of publication of application: (56) References cited: 06.04.2011 Bulletin 2011/14 EP-A- 1 018 340 CN-A- 1 534 013 CN-A- 1 543 933 JP-A- 6 009 479 (73) Proprietors: • Université Libre de Bruxelles • TANG BO ET AL: "Study on the supramolecular 1050 Bruxelles (BE) interaction of curcumin and beta-cyclodextrin by • Université de Liège spectrophotometry and its analytical 4000 Liège (BE) application" JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, AMERICAN CHEMICAL (72) Inventors: SOCIETY. WASHINGTON, US, vol. 50, no. 6, 13 • NEVEN, Philippe March 2002 (2002-03-13), pages 1355-1361, 4550 Nandrin (BE) XP002473288 ISSN: 0021-8561 • SERTEYN, Didier • BAGLOLE K N ET AL: "Fluorescence 4163 Tavier (BE) enhancement of curcumin upon inclusion into • DELARGE, Jacques parentand modified cyclodextrins" JOURNAL OF . (BE) PHOTOCHEMISTRY AND PHOTOBIOLOGY, A: • KISS, Robert CHEMISTRY, ELSEVIER SEQUOIA, LAUSANNE, 1600 St Pieters Leeuw (BE) CH, vol. 173, no. 3, 15 July 2005 (2005-07-15), • MATHIEU, Véronique pages 230-237, XP004965911 ISSN: 1010-6030 1150 Brussels (BE) • CATALDO, Didier Remarks: 4877 Olne (BE) Thefile contains technical information submitted after the application was filed and not included in this specification 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 2 303 328 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 303 328 B1 Description FIELD OF THE INVENTION 5 [0001] The invention relates to the medical field, more precisely the field of anti-cancer and anti-inflammatory treatment using new water soluble curcumin compositions. BACKGROUND OF THE INVENTION 10 [0002] Curcumin is the major curcuminoid of the Indian curry spice turmeric. Curcumin is known for its anti-oxidant, anti-arthritic, anti-amyloid and anti-inflammatory properties. In addition, over recent years, activity of curcumin against various types of cancer have been widely documented (Rao C.V. et al, Cancer Res.55, 259- 266, 1995, Kawamori et al, Cancer Res. 59, 597-601, 1999). [0003] While curcumin exhibits promising anti-cancer and/or anti-inflammatory properties, one of its major drawbacks 15 relates to its absorption, distribution and excretion in vivo. It has been described that blood levels of curcumin are always low after per os (oral) administration while they rise through intravenous injection. Besides that, it has been described that curcumin is totally metabolised in half an hour and that curcumin does not induce toxicity (Wahlström B. et al, Acta pharmacol. et toxicol .43, 86-92, 1978; Pan M.H.et al, Drug Metabolism and Disposition, 27,486-494, 1999, Ireson C. et al, Cancer Res.61, 1058-1064, 2001). 20 [0004] Although the level of activity found for curcumin and curcuminoid derivatives was and continues to be of high interest, this administered material does have significant deficiencies which indicates the continuing need for curcumin- complexes with improved properties. In the first place, curcumin was found to be insoluble in the majority of usual solvents. In addition, the plasma concentrations of curcumin after per os administration are either undetectable or very weak whatever the dosage level. Also, it seems that curcumin is quickly reduced (tetrahydrocurcumin, hexahydrocur- 25 cumin, hexahydrocurcuminol) and/or transformed (glucuronides or sulphates) in vivo. Thus, while curcumin and curcu- minoid derivatives show significant biological activity, they do not have physico-chemical properties suitable for further clinical development. The same shortcomings were observed for cyclodextrin complexes of curcuminoid derivatives as for salts of curcuminoid derivatives. [0005] In addition, although the pre-clinical activity of anti-proliferative agents such as curcumin itself or curcuminoid 30 derivatives against certain forms of cancers can be shown, improvement in tumour response rates, duration of response, decrease of toxicity and ultimately patient survival are still sought. [0006] Clinical data has furthermore indicated that patients displaying pulmonary inflammatory diseases have a higher incidence of developing lung tumours. This suggests that a persistent pulmonary inflammation might alter the organ’s properties to develop tumours, although the exact mechanisms connecting chronic inflammatory processes to cancer 35 are not yet well known. Until today, no treatment for precancerous lesions in the lungs exists. There is also no treatment available which can stop or slow down the formation of lung cancer in patients displaying an inflammatory disease in the airways. [0007] There is therefore an urgent need for identifying new active molecules displaying a potential interest for the treatment of inflammatory, precancerous or cancer diseases. 40 [0008] There is also a need in the art for improving the efficacy of anti-proliferative and anti-inflammatory treatments in humans and animals by providing suitable combinations of new drugs with conventional anti-neoplastic and/or anti- inflammatory agents. [0009] In view of the above-mentioned shortcomings of most of the agents used today in hospitals to treat cancer patients or patients with inflammatory disease, of known curcumin and curcuminoid derivatives, of salts of curcuminoid 45 derivatives and of cyclodextrin complexes of curcuminoid derivatives, there is a need in the art for new curcumin-derived compounds having enhanced physico-chemical properties and demonstrating a more promising activity/side effects balance. CN1534013 discloses water soluble lysine or arginine salts of curcumin compounds. CN543933 and JP06009479 disclose water soluble cyclodextrin complexes of curcumin. [0010] The aim was therefore to provide a new potential anti-proliferative and/or anti-inflammatory agent that is suitable 50 for per os administration. Simultaneously, said new agents were evaluated for their ability to modulate pulmonary in- flammation and/or lung cancer progression through trans-tracheal administration (e.g. inhalation). [0011] Our findings suggest that new curcumin-derivatives disclosed herein are interesting candidates for therapy against both proliferative and/or inflammatory disorders. Especially the increased solubility and prolonged stability of the curcumin-derivatives disclosed herein and their surprising activity via per os administration is very interesting and 55 unexpected. 2 EP 2 303 328 B1 SUMMARY OF THE INVENTION [0012] The scope of protection of the present invention is defined by the appended claims. [0013] Methods and compounds for treating proliferative and/or inflammatory disorders are disclosed. In particular, 5 water soluble and stable curcumin compositions or curcumin-derived compounds for treating proliferative and/or inflam- matory disorders are disclosed. Preferred water soluble curcumin compounds are compounds of general formula I: 10 15 wherein M is lysine or arginine and R1 and R2 are each independently selected from hydrogen, hydroxy or alkoxy, and/or 20 stereoisomers thereof. [0014] The preferred water soluble curcumin compounds are cyclodextrin complexes of the compounds of general formula I, and/or stereoisomers thereof. [0015] Even more preferred curcumin compounds are hydroxypropyl-beta-cyclodextrin (HP-beta-CD) or hydroxypro- pyl-gamma-cyclodextrin (HP-gamma-CD) complexes of the compounds of general formula I, i.e. the arginine or lysine 25 salts of curcumin. [0016] Most preferred compounds are a hydroxypropyl-beta-cyclodextrin complex of curcumin lysinate, called NDS27 hereinafter and a hydroxypropyl-gamma-cyclodextrin of curcumin lysinate, called NDS28 hereinafter. [0017] Curcumin used in the preparation of the water soluble curcumin compound as disclosed herein can be converted, resulting in the acylated derivative of curcumin or a derivative thereof or a glycosylated derivative. 30 [0018] The water soluble curcumin compounds as disclosed herein can be lyophilised. [0019] Alternatively, the water soluble curcumin compound as disclosed herein can be a cyclodextrin derivative of curcumin itself (i.e. not the lysine or arginine salt), preferably a beta or gamma-cyclodextrin derivative of curcumin, more preferably a gamma-cyclodextrin
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