(19) TZZ _T (11) EP 2 685 996 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A01N 65/00 (2009.01) A61K 36/00 (2006.01) 20.07.2016 Bulletin 2016/29 (86) International application number: (21) Application number: 11861334.8 PCT/IB2011/053962 (22) Date of filing: 10.09.2011 (87) International publication number: WO 2012/127287 (27.09.2012 Gazette 2012/39) (54) COMPOSITIONS AND METHODS FOR TREATING MULTI-DRUG RESISTANT MALARIA ZUSAMMENSETZUNGEN UND VERFAHREN ZUR BEHANDLUNG VON MULTIRESISTENTER MALARIA COMPOSITIONS ET MÉTHODES DE TRAITEMENT POUR UNE MALARIA RÉSISTANTE À DE MULTIPLES MÉDICAMENTS (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • SMITH, Garth Selwyn GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Guangxi 541004 (CN) PL PT RO RS SE SI SK SM TR • ZHANG, Lixin Designated Extension States: Beijing 100190 (CN) BA ME • DAI, Huanqin Beijing 100190 (CN) (30) Priority: 18.03.2011 US 201161454246 P (74) Representative: Held, Stephan (43) Date of publication of application: Meissner Bolte Patentanwälte 22.01.2014 Bulletin 2014/04 Rechtsanwälte Partnerschaft mbB Widenmayerstraße 47 (73) Proprietors: 80538 München (DE) • Febris Bio-Tech Limited 3204 Hamilton (NZ) (56) References cited: •Smith,Garth Selwyn EP-A1- 2 215 914 WO-A1-01/56959 Guilin, Guangxi 541004 (CN) WO-A2-2007/061912 WO-A2-2009/126950 • Zhang, Lixin US-A1- 2010 272 838 Beijing 100190 (CN) • Dai, Huanqin Beijing 100190 (CN) 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 2 685 996 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 685 996 B1 Description FIELD OF THE INVENTION 5 [0001] A method for treating an individual for a malarial infection is described. In particular, a method for treating an individual infected with a malarial drug-resistant species of Plasmodium, including administering to the individual in need of such treatment a composition containing one or more di- or tri-terpene compounds is disclosed. Potent and effective compounds derived from the fruit of Siraitia grosvenorii (Luo Han Guo) and the leaves of Stevia (Stevia rebaudiana), including combinations of the same, have been found to contain effective amounts of the di or tri-terpene compounds 10 and these are described. In one embodiment, the inventive composition is administered orally in a solid or liquid ingestible form. BACKGROUND 15 [0002] Malaria is a devastating infectious disease, and each year 350-500 million cases occur worldwide. As a major health concern in Asia, Africa, the Middle East, and Central and South America, about 41% of the world’s population live in areas where malaria is transmitted. And still more tragically, malaria causes 11% of all children’s deaths in developing countries. For example, the World Health Organization (WHO) reported that in 2008, malaria caused nearly one million deaths, mostly among African children. In Africa, a child dies every 45 seconds of malaria, and the disease 20 accounts for 20% of all childhood deaths. [0003] Antimalarial treatments, primarily drug therapies, are known. The quinines (or quinoline class), e.g. chloroquine, mefloquine, are well known as therapeutic agents. Other drug combinations have been developed as well. The best currently available treatment, particularly for P. falciparum malaria, is artemisinin-based combination therapy ("ACT"). Artemisinin is derived from a plant, Artemisia annul, which belongs to the Asteraceae family. 25 [0004] Unfortunately, two fundamental problems have arisen in the fight against malaria, namely, drug resistance and the high cost of drugs and medical treatments. There clearly exists an urgent need for alternative therapies that avoid the development of drug resistance by Plasmodium, and drastically lower the costs associated with treating malaria. It would be a contribution to the art of medicine to provide a readily available, easily accessible antimalarial composition administrable in various forms. 30 [0005] According to WHO data, if resistance to artemisinins develops and spreads to other large geographical areas, as has happened before with chloroquine and sulfacoxine-pyrimethamine (SP), the public health consequences could be dire, as it is possible that no alternative antimalarial medicines will be available in the near future. [0006] Furthermore, assuming that the same concentration of the extract from the fruit of Luo Han containing the composition of the present invention is as effective as that of artemisinin derivatives, the cost of the Luo Han extract 35 would be only a fraction of the cost per artemisinin treatment to cure malaria. The same could be said of Stevia leaf- based extracts. Even if a substantially greater amount of the active ingredients derived from Luo Han and/or Stevia were required for antimalarial treatments, the cost savings compared to currently marketed therapies would be immense. [0007] Certain di- and tri-terpene glycosides are known as sweeteners, but there have been no reports of using such compounds for treatment of malaria in a human subject. 40 [0008] It would be a further contribution to the art of medicine to provide a method of treating malaria by administering a composition containing one or more di- or tri-terpene compounds to a human patient in need of such treatment. It would be a further contribution to the art to provide a method of treating drug-resistant malaria by administering to a human patient in need of such treatment an effective amount of the composition of the invention in the form of an extract containing one or more di- or tri-terpene compounds. WO 01/56959 A1 discloses a substance including the chemical 45 structures of bicyclo[3.2.1]octan or the chemical structures of kaurene for the use in a dietary supplementation or as a constituent in a medicament for the treatment of non-insulin dependent diabetes mellitus, hypertension and/or the met- abolic syndrome. US 2010/0272838 A1 describes a method for the treatment and/or prophylaxis of a viral infection in a subject, wherein the method comprises the steps of providing a therapeutically effective amount of a composition com- prising an extract of the fruit of Siraitia grosvenori Swingle and administering the composition to the subject. The fruit 50 from which the extract is derived is Luo Han Guo. SUMMARY OF THE INVENTION [0009] Potent and effective active compounds derived from the fruit ofSiraitia grosvenorii (Luo Han Guo) and the 55 leaves of Stevia ( Stevia rebaudiana), including combinations of the same, have been found to contain effective amounts of one or more di- or tri-terpenes. These potent compounds including mogrosides can be extracted from Luo Han fruit. In one embodiment, assuming that the same concentration of the extract from Luo Han is generally as effective as that of artemisinin derivatives, then the cost of the Luo Han extract would be only a fraction of the cost per treatment to cure 2 EP 2 685 996 B1 malaria. Other potent compounds including rebaudioside A can be extracted from Stevia leaves. [0010] A method of treating an individual for a malarial infection is described, comprising administering to the individual in need of such treatment a therapeutically effective amount of a composition comprising a Stevia leaf extract containing steviol glycosides and an acceptable carrier. The present invention provides a composition comprising a Stevia leaf 5 extract containing steviol glycosides and an acceptable carrier for use in treating a malarial infection. [0011] In a further embodiment, a Luo Han fruit extract can be included in said composition for use in treating a malarial infection. Further, a method of treating an individual for a malarial infection is described, comprising administering to the individual in need of such treatment a therapeutically effective amount of a composition comprising a Luo Han fruit extract and an acceptable carrier. 10 [0012] Further is described a method of treating an individual for a malarial infection, comprising administering to the individual in need of such treatment a therapeutically effective amount of a composition comprising at least one of a di- terpene or a tri-terpene, and an acceptable carrier. [0013] Further is described a method of treating an individual for a malarial infection, comprising administering to the individual in need of such treatment a therapeutically effective amount of a composition comprising rebaudioside A, a 15 Luo Han fruit extract, and an acceptable carrier. [0014] In yet another embodiment, said composition further comprises a compound selected from the group consisting of mefloquine, halofantrine, artesunate, artemether, arteether, chloroquine, lumefantrine, primaquine, sulfadoxine, sul- falene, pyrimethamine, doxycycline, tetracycline, azithromycine, proguanil, cycloguanil, dapsone, artemisinin, dihydroar- temisinin and atovoquone, but preferably artemisinin. In yet another embodiment, the Stevia leaf extract contains one 20 or more di-terpene or tri-terpene glycosides selected from the group consisting of rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, rebaudioside F, dulcoside A, dulcoside B, rubusoside,