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(12) United States Patent (10) Patent No.: US 9.278,117 B2 Faizal Et Al

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(12) United States Patent (10) Patent No.: US 9.278,117 B2 Faizal Et Al US009278117B2 (12) United States Patent (10) Patent No.: US 9.278,117 B2 Faizal et al. (45) Date of Patent: Mar. 8, 2016 (54) COMPOSITION AND METHOD FOR THE JP 2007-195510 A 8, 2007 SAFE AND EFFECTIVE INHIBITION OF JP 2009-179579. A 8, 2009 PANCREATIC LIPASE IN MAMMALS JP 2010-202634 9, 2010 (71) Applicant: Bio Actives Japan Corporation, Tokyo OTHER PUBLICATIONS (JP) Yoshikawa et al. “Salacia reticulata arid Its Polyphenolic Constitu ents with Lipase Inhibitory and Lipolytic Activities Have Mild Anti (72) Inventors: Mohamed Faizal, Tokyo (JP); Hiroshi obesity Effects in Rats'. Journal of Nutrition, 2002, vol. 132, No. 7. Nishida, Tokyo (JP); Vladimir pp. 1819-1824. Badmaev, Staten Island, NY (US) Shimoda et al., “Effects of an Aqueous Extract of Salacia reticulata, a Useful Plant in Sri Lanka, on Postprandial Hyperglycemia in Rats (73) Assignee: Bio Actives Japan Corporation, Tokyo and Humans'. J. Jpn. Soc. Nutr. Food Sci., vol. 51, pp. 279-287 (JP) (1998). Yoshikawa, 2002, vol. 44, No. 12, pp. 26-30. (*) Notice: Subject to any disclaimer, the term of this Japanese Office Action issued in corresponding application No. patent is extended or adjusted under 35 2012-084645 on Nov. 19, 2013. U.S.C. 154(b) by 0 days. Japanese Office Action issued in corresponding application No. 2012-084645 on Aug. 5. 2014. (21) Appl. No.: 14/390,392 Li Y, et al. Salacia root, a unique Ayurvedic medicine, meets multiple targets in diabetes and obesity, Life Sciences, 2008, vol. 82, No. (22) PCT Filed: Apr. 1, 2013 21-22, p. 1045-1049. Filippatos TD, Derdemezis CS, Gazi IF. Nakou ES, Mihailidis DP. (86). PCT No.: PCT/UP2013/002252 Elisaf MS. Orlistat associated adverse effects and drug interactions: a critical review. Drug Suf 2008: 31(1): 53-65) S371 (c)(1), Badmaev V. Majeed A. Conte A. Parker JE. Diterpene Forskolin (2) Date: Oct. 2, 2014 (Coleus forskohlii, Benth.): A Possible new compound for reduction of body weight by increasinglean body mass. NutraCos vol. 1, No. 2 (87) PCT Pub. No.: WO2013/150771 (Mar. Apr.); 2002. Godard MP, Johnson BA. Richmond SR. Body composition and PCT Pub. Date: Oct. 10, 2013 hormonal adaptations associated with forskolin consumption in over weight and obese men, Obes Res Aug. 2005; 13(8): 1335-43. (65) Prior Publication Data http://www.fda.gov/Drugs/DrugSafety/ US 2015/OO56309 A1 Feb. 26, 2015 PostmarketDrugSafetyinformationforPatientsandProviders/ ucm213038.htm. (30) Foreign Application Priority Data Ellrichmann M. Kapelle M. Ritter PR, Holst J.J. Herzig KH. Schmidt WE, Schmitz F. Meier J.J. Orlistat inhibition of intestinal lipase Apr. 3, 2012 (JP) ................................. 2012-084645 acutely increases appetite and attenuates postprandial glucagon-like peptide-1-(7-36-amide-1, cholecystokinin, and peptide YY concen (51) Int. Cl. trations. J. Clin Endorinol. Metab. Oct. 2008: 93(10): 3995-8 Epub AOIN 65/00 (2009.01) Jul. 22, 2008. Duan RD, Erlanson-Albertsson C. Evidence of a stimulatory effect of A6 IK36/53 (2006.01) cyclic AMP on pancreatic lipase and colipase synthesis in rats. Scand A6 IK3I/352 (2006.01) J. Gastroenterol. Aug. 1992; 27(8): 644-8. A6 IK3I/36 (2006.01) WIPO/Japanese Patent Office, International Search Report, PCT/ A6 IK 45/06 (2006.01) JP2013/002252 mailed Jun. 25, 2013. A6 IK 36/37 (2006.01) A6 IK36/85 (2006.01) (52) U.S. Cl. Primary Examiner — Michael Meller CPC ............... A61K 36/53 (2013.01); A61 K3I/352 (74) Attorney, Agent, or Firm — Carter, DeLuca, Farrell & (2013.01); A61 K3I/36 (2013.01); A61 K Schmidt, LLP 36/185 (2013.01); A61K 36/37 (2013.01); A61K 45/06 (2013.01) (58) Field of Classification Search (57) ABSTRACT CPC ...................................................... A61K 36/00 USPC .......................................................... 424/725 Provided are a composition and method for the safe and See application file for complete search history. effective inhibition of pancreatic lipase in humans and other mammals. Provided is a composition which contains extracts (56) References Cited of one or more of Coleus forskohlii, Salacia reticulata, and Sesamum indicum, and which is administered orally to humans and other mammals in a nutritionally or pharmaco FOREIGN PATENT DOCUMENTS logically effective amount. Further provided is a method for JP 2000-309533. A 11, 2000 producing said composition. JP 2001-206893. A T 2001 JP 2004-091464 3, 2004 JP 2005-008572 A 1, 2005 7 Claims, 1 Drawing Sheet U.S. Patent Mar. 8, 2016 US 9.278,117 B2 i s 30, 3 girl & 3rri S. 30 giral n is 33 g/aria t a. O si...ws. ... literskelij4C8 Fig. 2 s & 3) #14 g (stand alone) is 2:g(Salacia stand alone) 34, insigt alaris tag US 9,278,117 B2 1. 2 COMPOSITION AND METHOD FOR THE As described above, current generation of pancreatic lipase SAFE AND EFFECTIVE INHIBITION OF inhibitors have potentially serious side effects and their effi PANCREATIC LIPASE IN MAMMALS cacy tend to decrease with prolonged use, i.e., tachyphylaxis and increases levels of appetite may cause diminishing their BACKGROUND OF THE INVENTION weight loss potential. 1. Field of the Invention PRIOR ART DOCUMENTS The present invention relates to a composition for safe and effective inhibition of pancreatic lipase and its use and a Non-Patent Documents method for producing said composition. 10 Non-Patent Document 1 http://www.fda.gov/Drugs/ 2. Description of the Related Art DrugSafety/PostmarketDrugSafety Informa Digestion and absorption of dietary fat are regulated by the tionforatientsand Providersfucm213038.htm action of pancreatic triglyceride lipase (PTL), and colipase Non-Patent Document 2 Filippatos TD, Derdemezis CS, which is a small protein cofactor and is needed by pancreatic Gazi I F, Nakou ES, Mikhailidis D. P. Elisaf MS. Orlistat lipase for efficient dietary lipid hydrolysis. The enzyme and 15 associated adverse effects and drug interactions: a critical cofactor are excreted from the pancreas to duodenum. PTL is review. Drug Suf 2008; 31(1): 53-65). the primary lipase that hydrolyzes dietary fat molecules in the Non-Patent Document 3 Ellrichmann M. Kapelle M, Rit human duodenum and converts triglyceride Substrates to ter PR, Holst JJ, Herzig KH, Schmidt WE, Schmitz F, Meier monoglycerides and free fatty acids. The resulting monomers J J Orlistat inhibition of intestinal lipase acutely increases (2 free fatty acids and one 2-monoacylglycerol) are packed appetite and attenuates postprandial glucagon-like peptide-1- into micelle and then absorbed into the lymphatic system by (7-36)-amide-1, cholecystokinin, and peptide YY concentra a specialized vessel called a lacteal. Colipase, an enzyme tions. JClin Endorinol Metab. 2008 October;93(10): 3995-8. belonging to family of pancreatic lipases, binds to the non Epub 2008 Jul. 22. catalytic domain of lipase, and increases stability and hydro Non-Patent Document 4 Badmaev V. Majeed A, Conte A, phobicity of the binding site. Colipase also prevents the 25 Parker J E. Diterpene Forskolin (Coleus forskohlii, Benth.): A inhibitory effect of various dietary factors on the lipase-cata possible new compound for reduction of body weight by lyzed hydrolysis of dietary long-chain triglycerides. increasing lean body mass. NutraCos Vol. 1, No. 2 (March/ April); 2002. Blocking the mechanisms of dietary fat digestion and Non-Patent Document 5 Godard MP Johnson BA, Rich absorption has been utilized in management of obesity. Inhi mond SR Body composition and hormonal adaptations asso bition of PTL activity with tetrahydrolipostatin (Orlistat/Xe 30 ciated with forskolin consumption in overweight and obese nical) and its diluted version, sold over-the-counter under the men. Obes Res 2005 August; 13(8): 1335-43. brand name of 'Alli', has been widely used in the pharmaco Non-Patent Document 6 Duan RD, Erlanson-Albertsson therapy of obesity. While tetrahydrolipostatin based products C Evidence of a stimulatory effect of cyclic AMP on pancre have been clinically proven as safe and effective, there are atic lipase and colipase synthesis in rats. Scand J Gastroen several known side effects and potential side effects of 35 terol. 1992 August; 27(8): 644-8. therapy. The primary side effects of the drug are gastrointestinal SUMMARY OF THE INVENTION tract-related, and include Steatorrhea (oily, loose stools with excessive intestinal putrefaction and flatus due to unabsorbed Problems to be Solved by the Invention fats reaching the large intestine), fecal incontinence, frequent 40 bowel movements and urgent bowel movements. The poten An object of the present invention is to provide a method tial organ toxicity of tetrahydrolipostatin has been signaled by and a composition for safe and effective inhibition of pancre the U.S. Food and Drug Administration (FDA). On May 26, atic lipase in humans and other mammal and a method for 2010, the FDA has approved a revised label for tetrahydroli producing said composition. postatin based drugs to include new safety information about 45 cases of liver injury that have been reported rarely with the Means for Solving the Problems use of this medication (Non-Patent Document 1). As a result of a devoted investigation, the present inventors The use of tetrahydrolipostatin has been associated with have found that each of Coleus forskohlii extract (hereinafter isolated cases of acute kidney injury, possibly due to the fat also referred to as “CF'), Salacia reticulata extract (herein malabsorption resulting from the excessive inhibition of pan 50 after also referred to as “SR), and Sesamum indicum extract creatic lipase, leading to the formation of Soaps of fatty acid (hereinafter also referred to as “SI) has pancreatic lipase with calcium and resulting in increased free oxalate absorp inhibition activity. The present inventors also have found that tion and hyperoxaluria (Non-Patent Document 2). a composition including at least one or more extracts safely Absorption of fat-soluble vitamins and other fat-soluble and effectively inhibits pancreatic lipase to accomplish the nutrients may be compromised with tetrahydrolipostatin, and 55 present invention.
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