US010517912B2 United States Patent ( 10 ) Patent No.: US 10,517,912 B2 Drewe et al. (45 ) Date of Patent : Dec. 31 , 2019 (54 ) PETASITES EXTRACT AND COMPOSITION (52 ) U.S. CI. AND METHOD FOR TREATING VIRAL CPC A61K 36/28 (2013.01 ) ; A61K 45/06 INFECTIONS (2013.01 ) ; A61K 2236/37 (2013.01 ) (58 ) Field of Classification Search (71 ) Applicant: Max Zeller Soehne AG , Romanshorn CPC A61K 36/28 (CH ) See application file for complete search history . ( 72 ) Inventors : Jurgen Drewe, Kreuzlingen (CH ) ; (56 ) References Cited Stephan Toff, Abtwil (CH ) ; Catherine Zahner , Romanshorn (CH ) FOREIGN PATENT DOCUMENTS ( 73 ) Assignee: MAX ZELLER SOEHNE AG , CN 103272130 9/2013 Romanshorn ( CH ) CN 103432457 10/2014 DE 19838848 3/2000 ( * ) Notice : Subject to any disclaimer , the term of this EP 1023079 8/2001 patent is extended or adjusted under 35 EP 1499334 1/2005 U.S.C. 154 ( b ) by 187 days . KR 2012-0027040 3/2012 (21 ) Appl. No.: 15 /563,367 OTHER PUBLICATIONS (22 ) PCT Filed : Mar. 15 , 2016 Vogl et al. , “ Ethnopharmacological in vitro studies on Austria's folk medicine — An unexplored lore in vitro anti- inflammatory activities ( 86 ) PCT No.: PCT/ EP2016 / 055551 of 71 Austrian traditional herbal drugs, ” Journal of Ethnopharmacol ogy 149 :750-771 , 2013.* $ 371 ( c ) ( 1 ) , Brattstrom , et al . ,, “ Petasites Extract Ze 339 (PET ) Inhibits Allergen (2 ) Date : Sep. 29 , 2017 induced TH2 Responses , Airway Inflammation and Airway Hyper ractivity in Mice” , 2010 , Phytother . Res ., 24 , 680-5 . ( 87 ) PCT Pub . No .: WO2016 / 156028 Christen and Fritz Vogtle , Organische Chemie_Von den Grundlagen PCT Pub . Date : Oct. 6 , 2016 sur Forschung , vol. 1., 36-37 , 1988 ( With Translation ) . (Continued ) (65 ) Prior Publication Data Primary Examiner Rosanne Kosson US 2018/0078594 A1 Mar. 22 , 2018 ( 74 ) Attorney , Agent, or Firm — Bryan D. Zerhusen , Esq .; Cantor Colburn LLP ( 30 ) Foreign Application Priority Data ( 57 ) ABSTRACT Apr. 1 , 2015 ( EP ) 15162229 The present invention relates to a Petasites extract or (51 ) Int. Ci. pharmaceutical composition thereof for use in a method for A61K 36/28 ( 2006.01) treating viral infections . A61K 45/06 (2006.01 ) 19 Claims, 5 Drawing Sheets 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 1 2 3 4 . 5 6 US 10,517,912 B2 Page 2 ( 56 ) References Cited Lee , J, et al. , “ Activation of Innate Immunity is Required for Efficient Nuclear Reprogramming ” , 2012 , Cell , 151, 547-558 . Nebel, et al ., “ Effective treatment of early allergic and late inflam OTHER PUBLICATIONS matory symptoms of allergic rhinitis with Ze 339 ( Tesalin® n ): Dumitru , et al . , “ Petasol Butenoate Complex (Ze 339 ) relieves Results of a non - interventional observational study ” , 2014 , Planta allergic rhinitis - induced nasal obstruction more effectively than Med . , 80 — P1C24 . desloratadine” , 2011, J. Allergy Clin . Immunol. , 127 , 1515-21 . Schapowal , et al. , “ Butterbur Ze 339 for the treatment of intermit Fortier, et al. , “ The Viral Mimic , Polyinosinic : Plycytidylic acid , tent allergic rhinitis ” , 2004, Arch . Otolaryngol. Head Neck Sur. , induces fever in rats via an interleukin - 1 -dependent mechanism ” , 130 , 1381-6 . 2004 , Am . J. Physiol . Regul . Intergr. Comp . Physiol. , 287 , R759-66 . Schapowal, et al. , " Randomised controlled trial of butterbur and Gitlin , L., et al ., “ Essential role ofmda - 5 in type I IFN responses to cetirizine for treating seasonal allergic rhinitis ” , Jan. 19, 2002 , BMJ, polyriboinosinic : Polyribocytidylic acid and encephalomyocarditis 324 , 1-4 . picornavirus” , 2008 , PNAS , 103, 8459-8464 . Schapowal , et al. , “ Treating intermittent allergic rhinitis : a prospec Kato H., et al. , “ Cell Type- specific involvementof RIG - I in antiviral tive, randomized , placebo and antihistamine -controlled study of response ” , 2005 , Immunity, 23 , 19-28 . butterbur extract Ze 339 ” , 2005 , Phytother . Res. , 19 530-7 . Kato , H., et al. , “ Length -dependent recognition of double - stranded Thomet , et al. , " Anit - inflammatory activity of an extract of Petasites ribonucleic acids by retinoic acid -inducible gene - I and melanoma hybridus in allergic rhinitis ” , 2 ( 2002 ) , Intern . Immunopharacol , pp . differentiation - associated gene 5 ” , 2008 , J. Exp . Med . 205 , 1601 997-1006 . 1610 . Brattstrom , et al. , " A newly developed extract (Ze 339 ) from Kaufeler, et al. , “ Efficacy and Satety of Butterbur Herbal Extract Ze butterbur (Petasites hybridus L.) is clinically efficient in allergic 339 in seasonal allergic rhinitis : Postmarketing surveillance study ” , rhinitis (hay fever ) ” , Phytomedicine , Gustav Fischer Verlag, Stut 2006 , Adv. Ther. , 23 , 373-84 . tgart , De. , vol. 10 , Jan. 1 , 2003, pp . 50-52 , XP004957128 . Keusch , et al. , “ Treatment of allergic Rhinitis with the special butterbur extract Ze 339 ” , 2004 , Ars Medici, pp . 509-515 . * cited by examiner U.S. Patent Dec. 31 , 2019 Sheet 1 of 5 US 10,517,912 B2 Fig . 1a 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 hannamed 2 3 4 . 5 6 Fig . 1b 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 automaatsenwww.no 0.3 0.2 0.2 0.1 0.1 krevend 2 w ..4 5 6 U.S. Patent Dec. 31 , 2019 Sheet 2 of 5 US 10,517,912 B2 Fig . 1c 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 01 0.1 2 3 4 . 5 Fig . 2 6000 TLR3 4000 T 2000 Tud 100 80 60 40 20 0 PolyIC mediumPoly IC + Tesalin U.S. Patent Dec. 31 , 2019 Sheet 3 of 5 US 10,517,912 B2 Fig . 3 TLR3 2000 mL/pg 1000 0 PolyIC mediumPoly IC + Tesalin Fig . 4 4000 TLR3 3000 ** 2000 1000 ???6d 100 80 604 T 40 20 0 PolyIC mediumPoly IC + Tesalin U.S. Patent Dec. 31 , 2019 Sheet 4 of 5 US 10,517,912 B2 Fig . 5 Fig . 6 250 600 TLR3 TLR3 200 400 150 T mLpg/ ???6d 100 200 50 0 0 PolyIC PolyIC mediumPoly IC + Tesalin mediumPoly IC + Tesalin Fig . 7 6000 TLR3 4000 mL/pg 2000 0 PolyIC medium PolyIC + Tesalin U.S. Patent Dec. 31 , 2019 Sheet 5 of 5 US 10,517,912 B2 Fig . 8 RIG - 1 / 4000 1DA5 3000 A pg/mL 2000 1000 0 mediumPolyIC LyoVec PolyIC LyoVec + Tesalin Fig 9 4000 RIG - 1 / MDA5 3000 2000 T pgmL/ 1000 1 100 80 60 T 40 20 0 medium PolyPolyICIC LyoVecLyoVec +Tesalin US 10,517,912 B2 1 2 PETASITES EXTRACT AND COMPOSITION Therefore , in a first aspect , the invention is directed to a AND METHOD FOR TREATING VIRAL Petasites extract for use in the treatment of a viral disease . INFECTIONS Generally , the term “ extract ” as used in the art and herein refers to any product of extraction regardless of the final CROSS -REFERENCE TO RELATED 5 chemical composition or physical form , e.g. liquid , viscous , APPLICATIONS pasty or solid . Of course , a plant extract for pharmaceutical use is understood to relate to a plant extract product com This application is a U.S. national entry of International prising the active plant agent( s ) in a physiologically effec Application PCT / EP2016 /055551 , titled : " PETASITES tive form and amount. Typically , a solvent- based extraction , EXTRACT AND COMPOSITION AND METHOD FOR 10 e.g. aqueous , non -aqueous , liquid , gaseous , critical gas , e.g. TREATING VIRAL INFECTIONS” , having an Interna sub- or supercritical carbon dioxide extraction , will result in tional filing date of Mar. 15 , 2016 ; which claims the benefit extracted components that are optionally separated from the of European Patent Application Serial No. EP 15162229.7 , remaining raw materials , e.g. separated from the remaining filed Apr. 1 , 2015 ; the entire contents of the aforementioned solid plant materials , and which components can optionally applications are hereby incorporated herein by reference . 15 be further processed , e.g. purified . A preferred and non The present invention relates to a Petasites extract or limiting exemplary protocol for the manufacture of a Peta pharmaceutical composition thereof for use in a method for sites extract for use in the present invention is described in treating viral infections. Example 1. Depending on the type and mode of extraction , a Petasites BACKGROUND AND FIELD OF THE 20 extract can also comprise toxic pyrrolizidine- alkaloids and INVENTION pyrrolizidine- alkaloid derivatives such as N -oxides to a varying extent. In a preferred embodiment, the Petasites Viral infections constitute a widely spread disease caused extract for use in the present invention is substantially free by a large number of different viruses. In animals , in of pyrrolizidine - alkaloids including any derivatives of pyr particular mammals , viral infections typically lead to 25 rolizidine- alkaloids such as, e.g. N -oxides . Substantially inflammation reactions in their hosts as part of the immune free of pyrrolizidine- alkaloids means that the Petasites defence response . Said inflammation reactions can cause extract comprises non - toxic amounts of pyrrolizidine -alka discomfort and , in certain cases, further medical complica loids, preferably s2 ppm pyrrolizidine- alkaloids , more pref tions in the infected subject. Hence , it is desirable to reduce erably sl ppm pyrrolizidine - alkaloids, most preferably no the inflammation brought about by viral infections. 30 pyrrolizidine -alkaloids . The plant Petasites is commonly also referred to as Generally , Petasites extracts can be distinguished into Butterbur and Petasites extracts can be gained from the polar and non -polar Petasites extracts . In a preferred plant, in particular from the leaves and /or the rhizome.