US 20060024397A9 (19) United States (10) Pub. N0.: US 2006/0024397 A9 (12) Patent Application Publication (48) Pub. Date: Feb. 2, 2006 Nair et al. CORRECTED PUBLICATION (54) DIETARY FOOD SUPPLEMENT Prior Publication Data CONTAINING NATURAL CYCLOOXYGENASE INHIBITORS AND (15) Correction of US 2005/0100622 A1 May 12, 2005 METHODS FOR INHIBITING PAIN AND See Filing Date INFLAMMATION (65) US 2005/0100622 A1 May 12, 2005 (76) Inventors: Muraleedharan G. Nair, Okemos, MI (US); David L. Dewitt, Okemos, MI Related US. Application Data (US); Haibo Wang, Fresno, CA (US); David W. Krempin, Temecula, CA (62) Division of application No. 10/084,575, ?led on Feb. (US); Dipak K. Mody, Temecula, CA 27, 2002, noW Pat. No. 6,818,234. (US); David G. Groh, Temecula, CA (US); Mary A. Murray, Irvine, CA Publication Classi?cation (US); Marc Lemay, Long Beach, CA (51) Int. Cl. (US); Yong Qian, San Diego, CA (US); A61K 31/7048 (2006.01) Audra J. Davies, Long Beach, CA A61K 31/353 (2006.01) (US); Robin Dykhouse, Newport A61K 35/78 (2006.01) Beach, CA (US) (52) US. Cl. ........................... .. 424/777; 514/27; 514/456 Correspondence Address: ALTICOR INC. ABSTRACT 7575 FULTON STREET EAST MAILCODE (57) 78-2G ADA, MI 49355 (US) The present invention describes food supplements that con tain one or more fruit extracts useful for pain relief and (21) Appl. N0.: 10/945,609 anti-in?ammation. The food supplements may be used to inhibit in?ammation mediated by cyclooxygenase and more (22) Filed: Sep. 21, 2004 particularly by cyclooXygenase-2. Patent Application Publication Feb. 2, 2006 Sheet 1 0f 5 US 2006/0024397 A9 1 PLANT SOURCE ‘ 3 V 4 EXTRA——C——T—+- TAN ' EXTRACTION ——£————+AKE > EXTRACT 6 r 2 7 DIFILTRATE ULTRAFILTRATION RETENTATE 2O . PERMEATE 9 ' v 5 1O DIFILTRATE REVERSE Q5MQ5|5 PARMEATE 30 v RETENTATE v _ v 8 CONCENTRATOR DRYING 50 40 l l CONCENTRATE POWDER 12 Fig.1 Patent Application Publication Feb. 2, 2006 Sheet 2 0f 5 US 2006/0024397 A9 VISUAL ANALOGUE SCALE PAIN RATING BEFORE'AND AFTER ONE OR TWO TABLETS BERRY BLEND MEANS i SE >_ 5 +0NE TABLET .; —I—TWO TABLET 2 5 3 Z 2 35 1 BEFbRE' AFT'ER Fig. 2 PERCENT PAIN RELIEF AFTER ONE OR TWO TABLETS BERRY BLEND MEANS iSE 100 E __ g 75- ____ E 5 so o\° 2s- ____ O ____ ONE TABLET TWO TABLET Fig.3 Patent Application Publication Feb. 2, 2006 Sheet 3 0f 5 US 2006/0024397 A9 BREAKDOWN OF PAIN EPISODES BYTYPE E60 2 55 LL] m 40 z 30 :1 20 < 10 - LL. C3 0 I I 1 °\ HEADACHE JOINT/MUSCULAR DYSMENORRHEA OTHER PAIN TYPES Fig. 4 TIME TO EFFECT AND OVERALL RATING IB'Y DOSE LEVEL (MEANS WITH 95% CI.) *p=.04 - 6O - [VERY GOOD O 5 60 min- I r<n Lu T- —GOOD :1 ght 45 min- T i gr? A I T a U21 ' _ -FA|R Z I: 30 mm_ ‘ l m 15 min POOR ONETABLET TWOTABLETS ONE TABLET TWOTABLETS TIME TO EFFECT OVERALL RATING Fig.5 Patent Application Publication Feb. 2, 2006 Sheet 4 0f 5 US 2006/0024397 A9 SUCROSE PERMEABILITY FOLLOWING IBUPROFEN AND BERRY BLEND p=.O4 01 100 __ E O5 75 F‘ ————" O: g5 50 —“f SE F lg. 6 Z 25 m D 0 IBUPROFEN BERRY BLEND 10 254 ‘iiiO" l I l NUI | l | | Al I I DIODE ARRAY 100- e 330 MO I I I Ml l | 1 | 4A]f | | I I DIODE ARRAY b 520 C %_ a d C i r | | | l l | | | I l I SCAN ES + 100" - BPI O/o_ H ‘ O0.00 | 5.00]— I 10.001 l 15.00l I 20.00| MI 25.00I I 30.00l I“35.00 Fig. 7 Patent Application Publication Feb. 2, 2006 Sheet 5 0f 5 US 2006/0024397 A9 BERRY BLEND DIODE ARRAY 100 254 DIODE ARRAY e 330 U “II I I DIODE ARRAY 520 . a I I MC 1 ' SCAN ES + BPI I II I ‘TIME 5.00 1000 15.00 20.00 25.00 30.00 35.00 Fig. 8 US 2006/0024397 A9 Feb. 2, 2006 DIETARY FOOD SUPPLEMENT CONTAINING guish betWeen COX-1 and COX-2 and are touted as having NATURAL CYCLOOXYGENASE INHIBITORS AND less of the side effects associated With normal NSAIDs. METHODS FOR INHIBITING PAIN AND INFLAMMATION [0006] As noted above, many consumers prefer natural substances to synthetic drugs. Therefore, it is clear that there is a need for a natural and pharmacologically acceptable RELATED APPLICATIONS composition for use in relieving or alleviating pain, in?am [0001] The present application is a continuation-in-part of mation, and the symptoms associated With these conditions. PCT Application Serial No. US00/23423 ?led Aug. 25, In addition, there is a need for a natural composition that 2000, Which is a continuation of US. Provisional Applica provides relief from pain and in?ammation With minimal tion Ser. No. 60/151,280 ?led Aug. 27, 1999 and US. side effects to the gastrointestinal system. The present inven Provisional Application Ser. No. 60/151,278 ?led Aug. 27, tion addresses that need by providing a dietary food supple 1999, all of Which are herein incorporated by reference. ment containing an extract from one or more anthocyanin containing plants having a native active fraction that BACKGROUND provides pain relief, anti-in?ammation activity, and/or pref erential COX-2 inhibition. The supplement contains an [0002] The present invention relates to dietary food amount of the fraction in a proportion by dry Weight of other supplements that are useful for the relief of pain or in?am components that signi?cantly exceeds a proportion of the mation, and also for the inhibition of biochemical pathWays fraction present by dry Weight in juice obtained from the related to pain or in?ammation transmission. These food plant material. In general, the active fraction includes ?a supplements contain ?avonoids, and more particularly, cer vonoids, and in particular, anthocyanins. tain anthocyanins. [0007] Unless otherWise speci?cally stated, all percent [0003] Today, many consumers seek natural alternatives to ages used in the speci?cation and claims are Weight per synthetic pharmaceutical products to aid With a variety of centages. ailments experienced during daily life. Thus, dietary food supplements containing natural substances such as St. Johns BRIEF DESCRIPTION OF THE DRAWING Wort, gingko biloba, ginseng, and others have recently been [0008] FIG. 1 shoWs a ?oW sheet of one embodiment of marketed for a variety of purposes. To date, hoWever, it is a process for obtaining and concentrating desirable antho believed that no product containing natural substances is cyanins from anthocyanin-containing plants. available to provide for the relief of pain and/or in?amma tion equivalent to non-steroidal anti-in?ammatory drugs [0009] FIG. 2 is a visual analogue scale rating pain (“NSAIDs”). intensity before and after taking one or tWo tablets of a berry blend supplement in accordance With the present invention [0004] At the present, pain and in?ammation are com and Example 7. monly treated by the use of aspirin, ibuprofen (Motrin®, Advil®), and other similar substances commonly knoWn as [0010] FIG. 3 shoWs the percentage of pain relief after NSAIDs. In?ammation is transmitted, in part, by a class of taking one or tWo tablets of a berry blend supplement in compounds knoWn as prostaglandins, Which are released by accordance With the present invention and Example 7. a host in response to mechanical, thermal, chemical, bacte [0011] FIG. 4 shoWs the breakdoWn of pain episodes by rial, and other insults (Moncada et al., Handbook of Exp. types for the clinical trial described in Example 7. Pharm. Vol 50-1, Springer Verlag, pp 588-616,1978; Sam uelsson, Science, 220: 568-575, 1983; Davies et al., Ann. [0012] FIG. 5 shoWs the time to effect pain relief and the Rev. Immunol. 2:335-357,1984). Prostaglandin synthesis is overall rating of one or tWo tablets of a berry blend supple accomplished in a stepWise manner by a ubiquitous complex ment in accordance With the present invention and Example of microsomal enZymes. The ?rst enZyme in this biosyn 7. thetic pathWay is prostaglandin endoperoxide synthase. This [0013] FIG. 6 shoWs the comparative sucrose permeabil enZyme also is referred to in the art as fatty acid cyclooxy ity of ibupro?n and a berry blend supplement in accordance genase. There are tWo isoforms of this enZyme knoWn as With the present invention and Example 7. cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX 2), respectively (Smith, Am. J. Physiol., 268:F181-F191, DETAILED DESCRIPTION OF THE 1992). INVENTION [0005] Although substances such as aspirin inhibit pros [0014] Prostaglandins (Which include PGE2, PGD2, PGF2, taglandin production and thus, pain and/or in?ammation, PGI2 and other related compounds) represent a diverse they may cause stomach problems and or ulcers. To address group of autocrine and paracrine hormones that are derived these problems, drugs have been developed to target speci?c from the metabolism of fatty acids. They belong to a family pain pathWays in the hope that some of the problems of naturally occurring eicosanoids (prostaglandins, throm associated With aspirin, ibuprofen, and other similar sub boxanes and leukotrienes) that are not stored as such in cells, stances Will be reduced if not completely eliminated. One but are biosynthesiZed on demand from arachidonic acid, a such drug is CelebrexTM, Which apparently targets a speci?c 20-carbon fatty acid that is derived from the breakdoWn of pain pathWay and thus, does not have some of the disad cell-membrane phospholipids.