USOO6818234B1 (12) United States Patent (10) Patent No.: US 6,818,234 B1 Nair et al. (45) Date of Patent: Nov. 16, 2004 (54) DIETARY FOOD SUPPLEMENT (58) Field of Search ................................. 424/725, 732, CONTAINING NATURAL 424/777; 514/816 CYCLOOXYGENASE INHIBITORS AND METHODS FOR INHIBITING PAN AND (56) References Cited NFLAMMATION FOREIGN PATENT DOCUMENTS (75) Inventors: Muraleedharan G. Nair, Okemos, MI JP O7101836 * 4/1995 (US); Haibo Wang, Fresno, CA (US); RO 113712 * 10/1998 David L. Dewitt, Okemos, MI (US); David W. Krempin, Temecula, CA OTHER PUBLICATIONS (US); Dipak K. Mody, Temecula, CA Hirschhorn, H. The Home Herbal Doctor. 1982. Publ: Perker (US); Yong Qian, San Diego, CA (US); Publishing Co., Inc. NY; pp. 52-53.* David G. Groh, Temecula, CA (US); Internet publication titled “Sanbucol Black Elderberry Audra J. Davies, Long Beach, CA Extract. The Original Nature Way” at www.betterlife.com; (US); Mary A. Murray, Irvine, CA first published on internet in 1996, 2 pages.* (US); Robin Dykhouse, Newport Internet publication titled “Elixir of Elderberry” at http:// Beach, CA (US); Marc Lemay, Long www.mothernature.com; first published on internet in 1995, Beach, CA (US) 2 pages. * Internet publication titled “Sambucol Black Elderberry” at (73) Assignees: Access Business Group International http://www.mothernature.com; first published on internet in LLC, Ada, MI (US); Michigan State 1995, 2 pages.* University, East Lansing, MI (US) Keville, K. Vegetarian times. 1990. No. 154, pp. 62-65.* (*) Notice: Subject to any disclaimer,- the term of this Brown, Jr., T. Tom Brown's Guide to Wild Edible and patent is extended or adjusted under 35 Medicinal Plants. 1985. Publ: Berkely Brooks, NY; pp. U.S.C. 154(b) by 0 days. 114-117. * cited by examiner (21) Appl. No.: 10/084,575 Primary Examiner-Christopher R. Tate (22) Filed: Feb. 27, 2002 (74) Attorney, Agent, or Firm-Lynn Schwenning Alticor Inc. Related U.S. Application Data (57) ABSTRACT (63) Continuation-in-part of application No. PCT/US00/23423, filed on Aug. 25, 2000. The present invention describes food Supplements that con (60) Provisional application No. 60/151,280, filed on Aug. 27, tain one or more fruit extracts useful for pain relief and 1999, and provisional application No. 60/151.278, filed on anti-inflammation. The food Supplements may be used to Aug. 27, 1999. inhibit inflammation mediated by cyclooxygenase and more (51) Int. Cl. ................................................ A61K 35/78 particularly by cyclooxygenase-2. (52) U.S. Cl. ....................... 424/777; 424/732; 424/725; 514/816 15 Claims, 5 Drawing Sheets U.S. Patent Nov. 16, 2004 Sheet 1 of 5 US 6,818,234 B1 1 PLANT SOURCE 3 EXTRACTANT 6 2 DFTRATE RETENTATE 20 PERMEATE 9. 5 10 DFLTRATE REVERSE OSMOSIS PARMEATE part visios RETENATE 8 SO 40 CONCENTRATE POWDER 2 11 Fig. 1 U.S. Patent Nov. 16, 2004 Sheet 2 of 5 US 6,818,234 B1 VISUAL ANALOGUESCALE PAIN RATING BEFORE AND AFTER ONE OR TWO TABLETS BERRY BLEND MEANSESE >- 5 to-ONE TABLET HTWO TABLET ZA 4 Z 3 Z 2 S - BEFORE AFTER Fig.2 PERCEN PAN RELEF AFTER ONE OR TWO TABLETS BERRY BLEND MEANSSE 100 75 Z 5 SO p 25 O ONE TABLE TWO TABLET Fig. 3 U.S. Patent Nov. 16, 2004 Sheet 3 of 5 US 6,818,234 B1 BREAKDOWN OF PAN EPISODES BYTYPE s: 30 20 L 10 O O s HEADACHE JONAMUSCULAR DYSMENORRHEA OTHER PANTYPES Fig. 4 TIMEO EFFECT AND OVERALL RAING BY DOSE LEVEL (MEANS WITH 95% C.I.) *p=.04 60 VERY GOOD 9 60 min GOOD SE O 45 mi s D g h FAR g 30 min I G 5 min POOR ONE TABLET TWO TABLETS ONEABLET TWO TABLETS TIME TO EFFECT OVERALL RATING Fig.5 U.S. Patent Nov. 16, 2004 Sheet 4 of 5 US 6,818,234 B1 SUCROSE PERMEABILITY FOLLOWING BUPROFENAND BERRYBLEND p=.04 on 100 E C 75 Sg 50 g Fig.6 2 25 f C O BUPROFEN BERRY BLEND EDERBERRY DiODE ARRAY O 254 % O OODE ARRAY 10 e 330 % f O DODE ARRAY O b A c 520 % d O SCAN ES + 10 BP % O TIME 0.00 5.00 0.00 5.00 20.00 25.00 3O.OO 35.00 Fig. 7 U.S. Patent Nov. 16, 2004 Sheet 5 of 5 US 6,818,234 B1 BERRY BLEND 100 DODE ARRAY 254 O I-1- OO DODEARRAY 330 % OL--- 100 DODE ARRAY b A c 520 96 O a d OO SCAN ES BP 96 O TME O.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 Fig.8 US 6,818,234 B1 1 2 DETARY FOOD SUPPLEMENT composition for use in relieving or alleviating pain, CONTAINING NATURAL inflammation, and the Symptoms associated with these con CYCLOOXYGENASE INHIBITORS AND ditions. In addition, there is a need for a natural composition METHODS FOR INHIBITING PAIN AND that provides relief from pain and inflammation with mini NFLAMMATION mal Side effects to the gastrointestinal System. The present invention addresses that need by providing a dietary food RELATED APPLICATIONS Supplement containing an extract from one or more The present application is a continuation-in-part of PCT anthocyanin-containing plants having a native active frac application Ser. No. PCT/US00/23423 filed Aug. 25, 2000, tion that provides pain relief, anti-inflammation activity, of U.S. Provisional Application Ser. No. 60/151,280 filed and/or preferential COX-2 inhibition. The Supplement con Aug. 27, 1999 and U.S. Provisional Application Ser. No. tains an amount of the fraction in a proportion by dry weight 60/151,278 filed Aug. 27, 1999, all of which are herein of other components that Significantly exceeds a proportion incorporated by reference. of the fraction present by dry weight in juice obtained from the plant material. In general, the active fraction includes BACKGROUND 15 flavonoids, and in particular, anthocyanins. The present invention relates to dietary food Supplements Unless otherwise Specifically Stated, all percentages used that are useful for the relief of pain or inflammation, and also in the Specification and claims are weight percentages. for the inhibition of biochemical pathways related to pain or inflammation transmission. These food Supplements contain BRIEF DESCRIPTION OF THE DRAWING flavonoids, and more particularly, certain anthocyanins. FIG. 1 shows a flow sheet of one embodiment of a process Today, many consumerS Seek natural alternatives to Syn for obtaining and concentrating desirable anthocyanins from thetic pharmaceutical products to aid with a variety of anthocyanin-containing plants. ailments experienced during daily life. Thus, dietary food FIG. 2 is a visual analogue Scale rating pain intensity Supplements containing natural Substances Such as St. Johns 25 before and after taking one or two tablets of a berry blend wort, gingko biloba, ginseng, and others have recently been Supplement in accordance with the present invention and marketed for a variety of purposes. To date, however, it is Example 7. believed that no product containing natural Substances is available to provide for the relief of pain and/or inflamma FIG.3 shows the percentage of pain relief after taking one tion equivalent to non-Steroidal anti-inflammatory drugs or two tablets of a berry blend Supplement in accordance (“NSAIDs"). with the present invention and Example 7. At the present, pain and inflammation are commonly FIG. 4 shows the breakdown of pain episodes by types for treated by the use of aspirin, ibuprofen (Motrin(R), Advil(R), the clinical trial described in Example 7. and other similar substances commonly known as NSAIDs. FIG. 5 shows the time to effect pain relief and the overall Inflammation is transmitted, in part, by a class of com 35 rating of one or two tablets of a berry blend Supplement in pounds known as prostaglandins, which are released by a accordance with the present invention and Example 7. host in response to mechanical, thermal, chemical, bacterial, FIG. 6 shows the comparative Sucrose permeability of and other insults (Moncada et al., Handbook of Exp. Pharm. ibuprofin and a berry blend Supplement in accordance with Vol 50-1, Springer Verlag, pp 588-616, 1978; Samuelsson, the present invention and Example 7. Science, 220: 568-575, 1983; Davies et al, Ann. Rev. 40 Immunol. 2:335-357, 1984). Prostaglandin synthesis is DETAILED DESCRIPTION OF THE accomplished in a stepwise manner by a ubiquitous complex INVENTION of microSomal enzymes. The first enzyme in this biosyn Prostaglandins (which include PGE, PGD, PGF, PGI thetic pathway is prostaglandin endoperoxide Synthase. This and other related compounds) represent a diverse group of enzyme also is referred to in the art as fatty acid cyclooxy 45 autocrine and paracrine hormones that are derived from the genase. There are two isoforms of this enzyme known as metabolism of fatty acids. They belong to a family of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX naturally occurring eicosanoids (prostaglandins, thrombox 2), respectively (Smith, Am. J. Physiol., 268:F181-F191, anes and leukotrienes) that are not stored as Such in cells, but 1992). are biosynthesized on demand from arachidonic acid, a Although Substances Such as aspirin inhibit prostaglandin 50 20-carbon fatty acid that is derived from the breakdown of production and thus, pain and/or inflammation, they may cell-membrane phospholipids. Under normal circumstances, cause Stomach problems and or ulcers. To address these the eicosanoids are produced at low levels to Serve as problems, drugs have been developed to target Specific pain important mediators of many and diverse cellular functions pathways in the hope that Some of the problems associated which can be very different in different types of cells. The with aspirin, ibuprofen, and other similar Substances will be 55 prostaglandins, however, also play critical roles in patho reduced if not completely eliminated.