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(12) Patent Application Publication (10) Pub. No.: US 2012/0329736A1 Huang Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0329736A1 Huang Et Al US 20120329736A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0329736A1 Huang et al. (43) Pub. Date: Dec. 27, 2012 (54) TREATMENT FOR GASTROINTESTINAL A6IPI/08 (2006.01) DISORDERS USINGA SELECTIVE, A6IPI/00 (2006.01) SITE-ACTIVATED BINDING SYSTEM A6IPI/2 (2006.01) A6IP3/00 (2006.01) (76) Inventors: Alexander L. Huang, Menlo Park, CA A6IPL/04 (2006.01) (US); Gin Wu, San Rafael, CA (US) A613 L/353 (2006.01) A6IP 29/00 (2006.01) (21) Appl. No.: 13/135,123 (52) U.S. Cl. ........................... 514/25: 514/456; 514/568 (22) Filed: Jun. 24, 2011 (57) ABSTRACT The teachings provided herein generally relate to site-acti Publication Classification vated binding systems that selectively increase the bioactivity of phenolic compounds at target sites. More particularly, the (51) Int. Cl. systems taught here include a phenolic compound bound to a A6 IK3I/7028 (2006.01) reactive oxygen species, wherein the phenolic compound and A6 IK3I/92 (2006.01) the reactive oxygen species react at a target area in the pres A6IP3I/00 (2006.01) ence of an oxidoreductase enzyme. Patent Application Publication Dec. 27, 2012 Sheet 1 of 13 US 2012/0329736A1 Graaix Growth retic Post Wean, 35 Days :::::::::::::::: i8:::::::::: Patent Application Publication Dec. 27, 2012 Sheet 2 of 13 US 2012/0329736A1 2 5 Sow ID LY32 LY421 LY38 LY52 Y410 Y35 | LD41 LY38 LD430 LY46 5 6 1. O 8 5 O Farrow 2/11 3/113 3 3 /11 4/11 date Party | | | | 2 | | | | | 3 | Born 10 10 7 10 9 12 11 7 9 alive - - an -- - day Gl s O G disorder diarrhea index + mild ++ moderate +++ severe FIG. 1B Patent Application Publica tion Dec. 27, 2012 Sheet 3 Of 13 US 2012/0329736A1 Patent Application Publication Dec. 27, 2012 Sheet 4 of 13 US 2012/0329736A1 Patent Application Publication Dec. 27, 2012 Sheet 5 of 13 US 2012/0329736A1 |(anbayaque Patent Application Publication Dec. 27, 2012 Sheet 6 of 13 US 2012/0329736A1 .................... Patent Application Publication Dec. 27, 2012 Sheet 7 of 13 US 2012/0329736A1 :*::::::::::::sssssssssssssssssssssss 8 x, i. &X-------------Xs-s-s-s-s-s-s-s-X-XXX------------------- Patent Application Publication Dec. 27, 2012 Sheet 8 of 13 US 2012/0329736A1 Patent Application Publication Dec. 27, 2012 Sheet 9 of 13 8:3 s:3 Patent Application Publication Dec. 27, 2012 Sheet 10 of 13 US 2012/0329736A1 &ō& Patent Application Publication Dec. 27, 2012 Sheet 11 of 13 US 2012/0329736A1 ********«& ***** Patent Application Publication Dec. 27, 2012 Sheet 12 of 13 US 2012/0329736A1 g§§§§§*****33.3 Patent Application Publication Dec. 27, 2012 Sheet 13 of 13 US 2012/0329736A1 $$$$$$$$$$ US 2012/032973.6 A1 Dec. 27, 2012 TREATMENT FOR GASTRONTESTINAL systems. As such, the art has still not found an effective way DISORDERS USING ASELECTIVE, to utilize the health improving potential of these natural phe SITE-ACTIVATED BINDING SYSTEM nolic compounds. 0007. One of skill would appreciate having a broad spec BACKGROUND trum system to bind compromised tissues, irritants and patho gens that includes these seemingly desirable phenolic com 0001 1. Field of the Invention pounds, particularly a system that (i) is stable, or at least 0002 The teachings provided herein relate to site-acti Substantially stable, for storage or administration; (ii) selec vated binding systems that selectively increase the bioctivity tively bioactivates the binding system at a target site without of phenolic compounds at target sites. significant indiscriminate complexing in undesirable loca tions; (iii) functions as an astringent, an antitoxin, an antimi 0003 2. Description of Related Art crobial, an antinflammatory, an anti-infectant, and the like, 0004 Some phenolic compounds, such as the polyphe reacting with pathogens, their virulence factors, pro-inflam nols, are considered beneficial for use as antioxidants in ani matory compounds and damaged host tissues; and, (iv) func mals, such as humans, due to their ability to Scavenge tions Surprisingly well in Small amounts on dermal, mucosal, unwanted reactive oxygen species in vivo. Such reactive oxy or in the GI tract tissue of an animal subject, whether human gen species can include, for example, singlet oxygen, peroX or non-human, aeorobic or anaerobic environments, to target ynitrite, and hydrogen peroxide. This ability to Scavenge and bind or exclude unwanted materials to treat health con these reactive oxygen species can affect cell-to-cell signaling, ditions, maintain health, and Supplement the health and nutri receptor sensitivity, inflammatory enzyme activity and even tion of the subject. gene regulation. An antioxidant molecule can, for example, inhibit the oxidation of molecules and are characterized as SUMMARY having a multiplicity of polar moieties that form bonds with 0008. The teachings provided herein generally relate to oxidizers such as hydrogen peroxide. site-activated binding systems that selectively increase the 0005 Nutritionists have long-recognized the unique bioactivity of phenolic compounds at a target site. health benefits of “live' uncooked fruits and vegetables in the 0009. The teachings include a binding system that selec diet. The main source of polyphenols for humans is currently tively increases the bioactivity of phenolic compounds at a dietary, since they are found in a wide array of phytochemi target site. In some embodiments, the system can include a cal-bearing foods. For example, honey; most legumes; fruits phenolic compound component and a reactive oxygen species Such as apples, blackberries, blueberries, cantaloupe, cher component. The phenolic compound component can com ries, cranberries, grapes, pears, plums, raspberries, and straw prise a tannin having a molecular weight ranging from about berries; and vegetables Such as broccoli, cabbage, celery, 500 Daltons to about 4000 Daltons; and, the reactive oxygen onion and parsley are rich in polyphenols. red wine, choco species component can comprise hydrogen peroxide. In some late, green tea, olive oil, argan oil, bee pollen and many grains embodiments, the hydrogen peroxide can be releasably are sources of these compounds. It is well known that many bound to the tannin at a tannin:peroxide weight ratio (a molar plant polyphenols ingested or otherwise introduced to animal weight ratio) that ranges from about 1:1000 to about 10:1. In physiology vary greatly in bioavailability and potency. More Some embodiments, the weight ratio of the tannin:peroxide over, many examples of traditional medicines using living or ranges from about 1:1 to about 1:50. And, in some embodi freshly harvested plant materials have only short lived ments, the binding system is bioactivated at a target site potency. In addition, all current extraction methods including having an oxidoreductase enzyme that is expressed in Solvent, reflux heating, Sonication, maceration and micro response to a tissue damage. In these embodiments, the phe wave techniques disrupt intracellular structures, triggering nolic compound component can bind to the target site selec mixing of oxidoreductase enzymes with polyphenols. The tively. Moreover, in some embodiments, the binding system polyphenols typically oxidize in the process and have a ten contains no, or Substantially no, unbound hydrogen peroxide dency to autopolymerize or complex indiscriminately with prior to the bioactivating at the target site. The teachings also other extracted compounds, destroying significant bioactive include a pharmaceutical formulation comprising the binding potential in a short period of time. Another problem is that systems taught herein and a pharmaceutically acceptable many medicinally useful polyphenol compounds also have excipient. poor bioavailability. Oxidized polyphenols typically have 0010. In some embodiments, the binding molecule com increased astringent binding activity but also have the ten prises a hydrolysable tannin. In some embodiments, the bind dency to complex indiscriminately with body tissues, body ing molecule comprises a condensed tannin. And, in some fluids, or foods in the digestive tract. In addition, another embodiments, the binding molecule comprises a combination problem is that bioactivation of the phenolic compounds of a hydrolysable tannin and a condensed tannin. requires reactive oxygen species and, in Some embodiments, 0011. In some embodiments, the phenolic compound the target site is an anaerobic physiologic environment, and component comprises a flavanol. In some embodiments, the the phenolic compound has difficulty activating. phenolic compound component comprises a catechin. And, in 0006. As a result of at least the above, studies have failed Some embodiments, the phenolic compound component to demonstrate definitive health benefits from dietary supple comprises gallic acid, epigallic acid, or a combination mentation with antioxidants, such as polyphenols. Others thereof. have even shown negative effects, including toxic effects 0012. The target site can be a damaged tissue of a subject. from an excessive ingestion of an antioxidant in an attempt to AS Such, the teachings include a method of treating a dam achieve the desired effects. And, most studies, at best, have aged dermal, mucosal, or gastrointestinal tissue. In some shown a low bioavailability and rapid excretion of orally embodiments, the method includes administering an effective ingested antioxidant polyphenol Supplements from in vivo amount of a binding system taught herein to the damaged US 2012/032973.6 A1 Dec. 27, 2012 tissue of the Subject. In some embodiments, the binding sys sisting of
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