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(12) United States Patent (10) Patent No.: US 8,551,507 B2 Liu (45) Date of Patent: Oct US008551507 B2 (12) United States Patent (10) Patent No.: US 8,551,507 B2 Liu (45) Date of Patent: Oct. 8, 2013 (54) TERPENE GLYCOSIDES AND THEIR Paeoniae Radix, and Increase of Water Solubilty of COMBINATIONS AS SOLUBLIZINGAGENTS Proanthocyanidins in the Presence of Paeoniflorin. Chem. Pharm. Bull 48(2), 2000, pp. 201-207.* (75) Inventor: Zhijun Liu, Baton Rouge, LA (US) Anne Marie Fine, Oligomeric Proanthocyanidin Complexes: His tory, Structure, and Phytopharmaceutical Applications. Alternative (73) Assignee: Board of Supervisors of Louisiana Medicine Review, vol. 5 No. 2, 2000, pp. 144-151.* State University And Agricultural and AMA Drug Evaluations Annual, “Clofazimine Lamprene. pp. Mechanical College, Baton Rouge, LA 1619-1620 (1993). (US) Eicher, Tet al., “Azole.” in The Chemistry of Heterocycles. Structure, Reactions, Syntheses, and Applications, Wiley-VCH. (2003). (*) Notice: Subject to any disclaimer, the term of this Kimata, H. et al., “Interaction of Saponin of Bupleuri Radix with patent is extended or adjusted under 35 Ginseng Saponin: Solubilization of Saikosaponin-a with Chikusetsu U.S.C. 154(b) by 0 days. saponin V (=Ginsenoside-Ro).” Chem. Pharm. Bull. (Tokyo), vol.33, pp. 2849-2853 (1985). Lipinski, C.A., “Drug-like Properties and the Causes of Poor Solu (21) Appl. No.: 13/379,072 bility and Poor Permeability.” J Pharm Tox Meth, vol. 44, pp. 235-249 (2000). (22) PCT Filed: Jun. 24, 2010 Lipinski, C., et al., “Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Devel (86). PCT No.: PCT/US2010/039799 opment Settings.” Adv. Drug Deliv. Rev., vol. 23, iss. 1-3, pp. 3-25 (1997). S371 (c)(1), Material Safety Data Sheet, “Artemisinin”. (2), (4) Date: Jan. 25, 2012 Material Safety Data Sheet, “Podophyllotoxin'. Material Safety Data Sheet, “Silybin (Silibinin)”. (87) PCT Pub. No.: WO2010/151653 Sasaki, Y. et al., “Solubilizing Properties of Glycyrrhizin and Its PCT Pub. Date: Dec. 29, 2010 Derivatives: Solubilization of Saikosaponin-a, the Saponin of Bupleuri Radix.” vol. 36, No. 9, pp. 3491-3495 (1988). (65) Prior Publication Data Tanaka, T. et al., “New Monoterpene Glycoside Esters and Penolic Constsituents of Paeoniae Radix, andlincreaase of Water Solubility of US 2012/O121696A1 May 17, 2012 Proanthocyanidins in the presence of Paeoniflorin.” Chem. Pharm. Bull., vol. 48, No. 2, pp. 201-207 (2000). Tanaka, T. et al., “Relationship between Hydrophobicity and Struc Related U.S. Application Data ture of Hydrolyzable Tannins, and Association of Tannins with Crude (60) Provisional application No. 61/219,973, filed on Jun. Drug Constituents in Aqueous Solution.” Chem. Pharm. Bull., vol. 24, 2009. 45, No. 12, pp. 1891-1897 (1997). Tanaka, T. et al., “Rubusoside (b-D-glucosyl ester of 13-O-b-D- (51) Int. Cl. glucosyl-Steviol), a Sweet principle of Rubus chingii Hu A6 IK3I/7048 (2006.01) (Rosacease).” Agricultural and Biological Chemistry, vol. 45, No. 9. pp. 2165-2166 (1981). A6 IK3I/337 (2006.01) The Merck Index, 12" Edition, Ed. S. Budavariet al., pp. 282-283 A6 IK3I/7034 (2006.01) (Camptothecin); 287-288 (Capsaicin); 450 (Curcumin); 737 (Gallic C7H 5/24 (2006.01) Acid); 894-895 (Itraconazole); and 1428 (Rutin) (1996). (52) U.S. Cl. USPC ............. 424/400; 424/777: 514/25; 514/449; * cited by examiner 514/450 (58) Field of Classification Search Primary Examiner — Frederick Krass None Assistant Examiner — Michael P Cohen See application file for complete search history. (74) Attorney, Agent, or Firm — John H. Runnels: Bonnie J. Davis (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Several terpene glycosides (e.g., mogroside V, paenoiflorin, 4,943,579 A 7, 1990 Vishnuvajala et al. ...... 514,283 5,635,611 A 6/1997 Ishiguro et al. ..... ... 536, 4.1 geniposide, rubusoside, rebaudioside A, Steviol monoside 6,673,843 B2 1/2004 Arbiser ........ 514f679 and stevioside) were discovered to enhance the solubility of a 2002/0076426 A1 6/2002 Zirnstein et al. ... 424/401 number of pharmaceutically and medicinally important com 2006,0003053 A1 1/2006 Ekanayake etal ... 426,51 pounds, including but not limited to, paclitaxel, camptoth 2007, OO32438 A1 2/2007 Hu et al. ............. 514/23 ecin, curcumin, tanshinone HA, capsaicin, cyclosporine, 2008/0242691 A1 10, 2008 Nakazawa et al. ... 514,283 erythromycin, nystatin, itraconazole, celecoxib, clofazimine, 2011/0195161 A1* 8/2011 Upreti et al. .................. 426,103 digoxin, oleandrin, nifedipine, and amiodarone. The use of FOREIGN PATENT DOCUMENTS the diterpene glycoside rubusoside and monoterpene glyco JP 58-101660 6, 1983 side paenoiflorin increased solubility in all tested com JP O1-299235 4f1989 pounds. The terpene glycosides are a naturally occurring JP 2001-048727 2, 2001 class of water Solubility-enhancing compounds that are non JP 2001.048727 A * 2, 2001 toxic and that will be useful as new complexing agents or WO WOf 2009 126950 10/2009 excipients in the pharmaceutical, agricultural (e.g., Solubiliz OTHER PUBLICATIONS ing pesticides), cosmetic and food industries. Takashi Tanaka, Maki Kataoka, Nagisa Tsuboi, and Isao Kouno. New Monoterpene Glycoside Esters and Phenolic Constituents of 40 Claims, 21 Drawing Sheets U.S. Patent Oct. 8, 2013 Sheet 1 of 21 US 8,551,507 B2 OCH 3 Curcumin 368 Tanshinone IIA294 Curcuminoid phenol OH Quinone O CO-Q10863 Quinone OH O ( O 0\ ^ O H OH O O OH OCH Y OCH, Silybin 482 OH Artemisinin282 o HO O Flavonolignan 0\, Sesquiterpene lactone Podophyllotoxin 414 Fic, F Lignan Fic, E 9. Fig 1D 9. O O Oleandrin 576 O Digoxin 780 C final Cardiac glycoside OH Cardiac glycoside HO H. H G HO / O N/\oyN-9s-4 YoY/Yo Ho Yo ho i0 Y H H Fig. 1G Fig, 1H U.S. Patent Oct. 8, 2013 Sheet 2 of 21 US 8,551,507 B2 OH it. t/ ch, ( OF HOH (H6H 0 t Y Y-ch. 3.11. o: HCOONa M. I./Y. M CH Camptothecin348 O Y., iv. HC O Quinoline alkaloid HC ^ | ych Paclitaxel 853 - Ampholericin B924 OCH, Fig Taxane Diterpene Microllide H.N-OH Fig, J Fig. K CH, OH CH, C Clofazimine 473 Riminophenazine CH; CH, Y,\ it CeleCOxib38 e F Propofol 178 NYA. Fig. 4L Go Fia. M ^^ F. CoolFig Fig.1N NO, : OH,C-C C-OCH, OCHCHNCHCH N/ 0 Nifedipine 346 \ AmiodarOne 645 ^ Dihydropyridine CHCHCHCH. Furan H.C N: CH, O Fig, 10 Fig, 1P U.S. Patent Oct. 8, 2013 Sheet 3 of 21 US 8,551,507 B2 OH Mogroside V OAC Astragaloside IV OH U.S. Patent Oct. 8, 2013 Sheet 4 of 21 US 8,551,507 B2 HO CHOn 20 O E O O HO CHOH O O 0 H OH O OH GenipOside Paeoliflorin OH Fig. 2C Fig. 2D U.S. Patent Oct. 8, 2013 Sheet 5 of 21 US 8,551,507 B2 H HO O OH HO O O OH O Stevioside Fig. 3A Fig. 3B U.S. Patent Oct. 8, 2013 Sheet 6 of 21 US 8,551,507 B2 HO OH O HO OH OH O OH Rebaudioside -0 SteviolmOnOside HO OH Fig. 3C Fig. 3D U.S. Patent Oct. 8, 2013 Sheet 7 of 21 US 8,551,507 B2 Curcumin O36 O27 O.O. wCUR6 CUR5 CUR4 CUR3 CUR CUR 20 280 50 420 490 B6 30 700 to 840 Minutes Fig. 4 U.S. Patent Oct. 8, 2013 Sheet 8 of 21 US 8,551,507 B2 3. 8 “renewauw“wswww.s.l...rew-ways errorway.' Ney'." . , '... w www.'i '"raw"westwytoves g; 23: 48 BCC 8 OCC 200 BC 5). it: 8 Fig.5 U.S. Patent Oct. 8, 2013 Sheet 9 of 21 US 8,551,507 B2 Paclitaxel 100 to 750 of 3. t 2 : 3. 100. 1200 - 0. 600 800 2008 Miyas Fig 6 U.S. Patent Oct. 8, 2013 Sheet 10 of 21 US 8,551,507 B2 O50 0.48 O46 O44 O42 0.40 O38 0.36 O34 O32 O3O O28 O26 ; : 024 Tanshinone IIA g O22 : O20 0.18 0.16 O.14 O. 12 0.10 0.08 0.06 004 0.02". OOOo -002 -004 OOO 2.OO 4OO 6OO 800 OOO 1200 14 OO 16 OO 18OO 20 OO 22 OO 20 260 28 OO 3OOO 32OO 3400 Minutes Fig. 7 U.S. Patent Oct. 8, 2013 Sheet 11 of 21 US 8,551,507 B2 Amphotericin B Minutes Fig. 8 U.S. Patent Oct. 8, 2013 Sheet 12 of 21 US 8,551,507 B2 to Artemisinin -OOO OOO 200 400 800 800 OOO 12 OO 1400 1600 1800 20 OO 2200 24 OO 26 OO 2800 3OOO 3200 3400 Minutes Fig, 9 U.S. Patent Oct. 8, 2013 Sheet 13 of 21 US 8,551,507 B2 Podophytotoxin : 20: . E is 18 to 22, 20 30 3. Rigtes Fig. 10 U.S. Patent Oct. 8, 2013 Sheet 14 of 21 US 8,551,507 B2 O2OO O. 190 0.18O O 170 0.160 O150 0,140 0.130 O. 120 OO OOO o O080 OOTO OO60 0.050 0.040 0.030 OO20 OOO OOOO. -OOO -0,020 OOO 2.00 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000 3200 34.00 Minutes Fig. 1 U.S. Patent Oct. 8, 2013 Sheet 15 of 21 US 8,551,507 B2 400 380 360 340 320 300 280 : 260 Propofol 220 s 2OO 180 Bo 140 120 1OO O80 O60 O40" 020." OOOT OOO 2 OO 4OO 600 8 OO 10 OO 12 OO 1400 1600 18 OO 2000 22 OO 2400 26 OO 28 OO 3OOO 32OO 3400 Minutes Fig 12 U.S. Patent Oct. 8, 2013 Sheet 16 of 21 US 8,551,507 B2 2 .
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