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6746695.Pdf (2.276Mb) US006746695B1 a2, United States Patent (10) Patent No.: US 6,746,695 B1 Martin et al. (45) Date of Patent: Jun. 8, 2004 (54) PHARMACEUTICAL PREPARATIONS OF Abad, MJ et al., Anti-inflammatory activity of some medici- BIOACTIVE SUBSTANCES EXTRACTED nal plant extracts from Venezuela. J. Ethnopharmacol1996 FROM NATURAL SOURCES Dec;55(1):63-8. Alarcon—Aguilara, FJ, et al., Study of the anti-hyperglyce- (75) Inventors: Michael Z. Martin, Laupahoehoe, HI mic effect of plants used as antidiabetics. J. Ethnopharmacol (US); Mehdi Ashraf-Khorassani, 61 2:101-110 (1998). Blacksburg, VA (US); Larry Taylor, Blacksburg, VA (US) Almeida CE et al., Analysis of anti—diarrheic effect of plants used in popular medicine. Rev Saude Publica 1995 (73) Assignees: Armadillo Pharmaceuticals, Inc., Dec;29(6):428-33. Armocas, CA (US); Virginia Tech. Alves KB, et al., Inhibition of aminopeptidase activity by Intellectual Properties, Inc., aromatic and other cyclic compounds. Braz J Med Biol Res. Blackburg, VA (US) 1992;25(11):1103-6. Anesini C, et al., Screening of plants used in Argentine folk (*) Notice: Subject to any disclaimer, the term of this medicine for anti-microbial activity. J Ethnopharmacol. patent is extended or adjusted under 35 1993 Jun;39(2):119-28. US.C. 154(b) by 0 days. Arletti, R, et al., Stimulating property of Turnera diffusa and (21) Appl. No.: 09/578,849 Pfaffia paniculata extracts on the sexual behavior of male rats, Psychopharmacology (Berl). 1999 Mar;143(1):15-9. (22) Filed: May 26, 2000 Auterhoff, H et al., Constituents of the drug Damiana. Arch Pharm (Weinheim) 301:537-544(1968). Related U.S. Application Data Ballot D, et al., The effects of fruit juices and fruits on the (63) Continuation-in-part of application No. 09/518,191, filed on absorption of iron from a rice meal. Br J Nutr. 1987 Mar. 3, 2000, now abandoned, and a continuation-in-part of May;57(3):331-43. application No. 09/408,922, filed on Sep. 30, 1999, now abandoned. Batista IF et al., Primary structure of a Kunitz—type trypsin (60) Provisional application No. 60/136,409, filed on May 27, inhibitor from Enteroloubium contorlisiliquum seeds. Phy- 1999, provisional application No. 60/122,526, filed on Mar. tochemistry. 1996 Mar;41(4):1017-22. 3, 1999, and provisional application No. 60/102,912, filed on Oct. 2, 1998. Becerra JX, et al., Nuclear ribosomal DNA phylogeny and its implications for evolutionary trends in Mexican Bursera (SL) Tint, Cn? eee eeeeeeeeeteeenesneeneeeneeneenees A61K 35/78 (Burseraceae) Am J Bot 1999 Jul;86(7):1047. (52) US. Ce ceecccccccceccssse 424/734; 424/725; 424/773; Bejar et al., International J. Pharmacognosy 33(1), 1995, pp. 210/656; 210/690; 210/691; 210/692 25-32. (58) Field of Search oo... eee 424/725, 734, 424/773; 210/656, 690, 691, 692 (List continued on next page.) (56) References Cited Primary Examiner—¥rancisco Prats U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm—Morrison & Foerster LLP 4,148,928 A 4/1979 Sodini et al. (57) ABSTRACT 4,209,539 A 6/1980 Banigan et al. 4,985,265 A 1/1991 Duboc et al. This invention relates to methods of extracting and purifying 5,120,558 A 6/1992 Nguyen et al. bioactive substances from various plants and herbs. More 5,296,224 A * 3/1994 Schwabe 424/195.1 specifically the invention relates to methods of extracting 5,440,055 A * 8/1995 Castor veces 549/510 and separating bioactive substances from various plants and 5,512,285 A 4/1996 Wilde herbs, such as Kava root, Byrsonima species, Aesculus 5,672,371 A 9/1997 d’Oosterlynck californica, Crataegus mexicana, Simmondsia chinensis, 5,750,709 A * 5/1998 Castor 0... eeeeeeeeeee 546/348 Pfaffia species, A/rernanthera repens, Bursera species, Turn- 5,925,355 A 7/1999 Chatterjee et al. 5,962,043 A 10/1999 Jones et al. era species, Perezia species, Heimia salicifolia, Psidtum 6,007,823 A 12/1999 Abbott et al. species, Enterlobium species, Ptychopetalum olacoides, 6,013,304 A 1/2000 Todd Liriosma ovata, and Chaunochiton kappleri, using super- 6,245,364 B1 6/2001 Jones et al. critical fluid extraction and/or fluorocarbon solvent extract. The present invention further relates to separation of bioac- FOREIGN PATENT DOCUMENTS tive substances contained in extracts using packed column GB 2 288552 10/1995 supercritical fluid chromatography or HPLC where dense WO 95/26795 10/1995 gas with or without modifiers is the mobile phase. The present invention also relates to pharmaceutical preparations OTHER PUBLICATIONS and dietary supplements which may be prepared with the Berger et al, J. Pharmaceutical Sciences, 83(3):281-286, extracted bioactive substances and use of such pharmaceu- 1994,* tical preparations and dietary supplements to treat various Bejar et al, Int. J. Pharmacognosy 33(1):25-32, 1995.* human ailments. Lopez—Avila et al, J. High. Resol. Chromatogr. 20:555-559, 1997.* 21 Claims, 33 Drawing Sheets US 6,746,695 B1 Page 2 OTHER PUBLICATIONS Jairaj, P et al., Anti-cough and antimicrobial activities of Psidium guajava Lion. Leaf extract. J Ethnopharmacol. Bianchi E, et al., Antitumor agents from Bursera fagroides 1999 Nov 1;67(2):203-12. (Burseraceae) (Beta—peltatin-A—methylether and 5’ Jolad SD, et al., Cytotoxic agents from Bursera klugii desemethoxy—beta—peltatin-Am-—methylether) 1969 Jul; (Burseraceae) I: isolation of sapelins A and B.J Pharm Sci 32:2759-62. 1977 Jun: 66(6):889-90. Bianchi E, et al., Antitumor agents from Bursera micro- Jolad-SD, et al., Cytotoxic agents from Bursera morelensis phylla (Burseraceae) I. Isolation and characterization of (Burseraceae) deoxypodophyllotoxin and a new lignan, deoxypodophyllotoxin. J Pharm Sci 1968 Apr;57(4):696-7. 5'-desmethoxydeoxypodophyllotoxin. J Pharm Sci 1977 Bocek, BR, Ethnobotany of Costanoan Indians, California, Jun:66(6):892-3. based on collections by John P. Harrington. Econ Bot 38 Kubo, I et al., Combined effect on plant growth of (—)-Epi- 1984 2:240-255. catchin and Hydroquinone, compounds from Aesculus cali- Caceres A, et al., Plants used in Guatemala for the treatment fornica Nutt. Chem Pharm Bull 33 1985 9:3826-3828. of gastrointestinal disorders. 1. Screening of 84 plants Kubo, I; Ying, BP, Phenolic constituents of California buck- against enterobacteria. J Ethnopharmacol. 1990 eye fruit. Phytochemistry 31 1992 11:37933-3794. Aug;30(1):55-73. Le Grand A, [Anti-infective phytotherapies of the tree—sa- Caceres A., et al., Plants used in Guatemala for the treatment vannah, Senegal (occidental Africa). III. A review of pho- of gastrointestinal disorders. 3. Confirmation of activity tochemical substances and the anti microbial activity of 43 against enterobacteria of 16 plants. J Ethnopharmacol. 1993 species]. J Ethnopharmacol. 1989 May;25(3):315-38. Jan;38(1):31-8. Review. French. Caldwell, ME, Brewer, WR, Plants with potential to enhance Lema, WJ et al., Prostaglandin synthetase inhibition by significant tumor growth. Cancer Res 43 1983 alkaloids of Heimia salifcifolia. J Ethnopharmacol 1986 12:5775-5777. Feb;15(2):161-7. Carabez, A. et al., The action of the sesquiterpenic benzo- Leon de Pinto G, et al., Chemical and 13C NMR studies of quinone, perezone on electron transport in biological mem- Enterolobium cyclacarpum gum and its degradation prod- branes. Arch Biochem Biophys. 1988 Jan;260(1):293-300. ucts. Phytochemistry. 1994 Nov;37(5):1311-5. Castr—-Faria—Neto HC et al., Pro—inflammatory activity of Lozoya X, et al., Quercetin glycosides in Psidium guajava enterolobin: a hemolytic protein purified from seeds of the L. leaves and determination of a spasmolytic principle. Arch Brazilian tree Enterolobium contortisiliquum. Toxicon. Med Res. 1994 Spring;25(1):11-5. 1991;29(9):1143-50. Lutterodt GD, Inhibition of Microlax—induced experimental diarrhea with narcotic—like extracts of Psidium guajava leaf Cheng, JT et al., Hypoglycemic effect of guava juice in mice and human subjects. Am Chin Med. 1983;11(104):74-6. in rats. J Ethnopharmacol 1992 Sep;37(2):151-7. Lutterodt GD, Inhibition of gastrointestinal release of ace- Costa RH et al., Purification and partial characterization of tylcholine by quercetin as a possible mode of action of Enterolobium contortisiliquum seed arylamidase. Braz J Med Bio Res. 1991;24(4):337-44. Psidium guajava leaf extracts in the treatment of acute diarrheal disease. J Ethnopharmacol 1989 de Sousa MV, et al, Enterolobin, a hemolytic protein from May;25(3):235-47. Enterolobium contortisilquum seeds (Leguminosae—Mimo- Lutterodt GD et al., Effects on mice locomotor activity of a saideae). Purification and characterization. An Acad Bras narcotic like principle from Psidium guajava leaves. J Cienc. 1989 Dec;61(4):405-12. Ethnopharmacol. 1988 Dec;24(2-3):219-31. Diaz, JL, Ethnopharmacology of sacred psychoactive plants Malone, MH, et al., Heimia salicifolia: a phytochemical and used by the Indians of Mexico. Ann Rev Pharmacol Toxicol phytopharmacologic review. J Ethnopharmacol 1994 17:647-(1977). May:;42(3):135-59. Dimayuga, RE; Murillo, RF; Pantoja, ML, Traditional medi- Matsuo, T et al., Identification of (+)-gallocatchin as a cine of Baja, California, Sur (Mexico II). J Ethnopharmacol bio—anti-mutagenic compound in Psidium guava leaves. 20 3:209-222 (1987). Phytochemistry 1994 Jul;36(4)1027-9. Enriquez, R. et al., Active components in Perezia roots. J Mazzanti, G, et al., Pharmacol Res 27 Anti—inflammatory Ethnopharmacol. 1980 Dec;2(4):389-93. activity of Pfaffia paniculata (Martius) Kuntze and Pfaffia Evans, MA, Ecology and removal of introduced rhesus stenophylla (Sprengel) Stuchl.1:91-92 (1993). monkeys; Desecheo Island National Wildlife Refuge, Puerto Mazzanti, G. Braghiroli, L, Analgesic and anti-inflamma- Rico, PR Health Sci J 1989 Apr; 8(1):139-56.
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