US 201403701 18A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/03701 18 A1 HUANG et al. (43) Pub. Date: Dec. 18, 2014

(54) METHODS OF TREATING MALNUTRITION Publication Classification (71) Applicant: LiveLeaf, Inc., San Carlos, CA (US) (51) Int. Cl. A61E36/82 (2006.01) (72) Inventors: ALEXANDER L HUANG, Menlo Park, A6II 45/06 (2006.01) CA (US); Gin Wu, San Rafael, CA (US) A63L/92 (2006.01) A613 L/7028 (2006.01) A633/40 (2006.01) (21)21) Appl. NoNo.: 14/317,9709 A61E36/85 (2006.01) (52) U.S. Cl. (22) Filed: Jun. 27, 2014 CPC ...... A61K 36/82 (2020.01); A61K 33/40 (2020.01); A61K 36/185 (2020.01); A61 K Related U.S. Application Data 31/192 (2020.01); A61 K3I/7028 (2020.01): A61K 45/06 (2020.01) (63) Continuation of application No. 14/272,047, filed on USPC ...... 424/616 May 7, 2014, now Pat. No. 8,809,399, which is a continuation of application No. 14/222,605, filed on (57) ABSTRACT Mar. 22, 2014, now Pat. No. 8,772,352, which is a Methods of treating malnutrition are provided, such methods continuation of application No. 14/173,079, filed on not requiring the use of systemic drugs that have shown to (i) Feb. 5, 2014, now Pat. No. 8,772,350, which is a con provide slow relief, (ii) cause adverse side effects, (iii) limit tinuation of application No. 14/142,895, filed on Dec. activities, (iv) worsen existing gastrointestinal conditions, (v) 29, 2013, now Pat. No. 8,716,353, which is a continu be unrecommended in several gastrointestinal conditions that ation of application No. 13/726, 180, filed on Dec. 23, include gastrointestinal spasms, or (vi) be unrecommended in 2012, now Pat. No. 8,716,351. the absence of diarrhea. Patent Application Publication Dec. 18, 2014 Sheet 1 of 4 US 2014/03701 18 A1

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METHODS OF TREATING MALNUTRTION 0007. A condition of particular interest in the treatment of gastrointestinal spasms is irritable bowel syndrome (IBS), a CROSS-REFERENCE TO RELATED condition afflicting an estimated 30 million people in the US APPLICATIONS and up to 700 million people worldwide. IBS is diagnosed from clinical symptoms that include abdominal pain, bloat 0001. This application is a continuation of U.S. applica ing, constipation, and diarrhea. Treatment options are based tion Ser. No. 14/272,047, filed May 7, 2014, which is a con upon the predominant symptom, with diarrhea-predominant tinuation of U.S. application Ser. No. 14/222,605, filed Mar. IBS receiving antidiarrheal agents, such as loperamide (IM 22, 2014, which is a continuation of U.S. application Ser. No. MODIUM) and pain-predominant IBS patients receiving 14/173,079, filed Feb. 5, 2014, which is a continuation of U.S. antispasmodic agents, such as dicyclomine HCL (BEN application Ser. No. 14/142,895, filed Dec. 29, 2013, now TRYL) and hyoscyamine sulfate (LEVSIN). The condition is U.S. Pat. No. 8,716,353, which is a continuation of U.S. generally thought to be the result of spasmodic contractions application Ser. No. 13/726,180, filed Dec. 23, 2012, now of the intestines that interfere with normal peristalsis causing U.S. Pat. No. 8,716.351, each of which is hereby incorporated blockages that lead to bloating and constipation, cause hyper herein by reference in its entirety. peristaltic activity leading to frequent need for defecation, or a combination. Problems with loperamide are discussed BACKGROUND above. Dicyclomine has the problem of some people sweat 0002 1. Field of the Invention less, allowing the body to overheat which can cause heat 0003. The teachings provided herein relate to methods of prostration (fever and heat stroke). As such, anyone taking treating malnutrition by treating associated gastrointestinal this drug should try to avoid extreme heat. Moreover, dicy Spasms. clomine can also cause drowsiness and blurred or double 0004 2. Description of Related Art vision, Such that people who take this drug should not drive, 0005 Antispasmodics can be used to prevent spasms of use machines, or do anything else that might be dangerous. the stomach, intestine, uterus, or urinary bladder. Gastrointes Hyoscyamine can also be used but, unfortunately, both dicy tinal spasms, for example, can be very painful. Abdominal clomine and hyoscyamine have general side effects and, for pain and discomfort from cramping, bloating, forceful vom example, can worsen gastroesophageal reflux disease. Anti iting, and forceful defecation are often the result of spasmodic cholinergics, generally speaking, are also known to cause intestinal contractions. The problem is that there is no satis difficulty in passing urine, and children and the elderly are at factory treatment to relieve the pain and suffering that cur a higher risk of developing Such side effects. rently exists due to this problem. Spasms can also be treated 0008. One of skill would appreciate having a method of using “anticholinergics” that counteract the effects of the treating spasms, particularly gastrointestinal spasms, without neurohormone acetylcholine. The anticholingergics decrease having to use systemic drugs that have shown to (i) provide both the movements of the stomach and intestine, and also the slow relief, (ii) cause adverse side effects, (iii) limit activities, secretions of stomach acid and digestive enzymes. Problems (iv) worsen existing gastrointestinal conditions, (v) be unrec with these drugs include dry mouth and dry eyes because of ommended in several gastrointestinal conditions that include reduced salivation and tearing. gastrointestinal spasms, and (vi) be unrecommended in the 0006 An example of an anticholinergic that is used to treat absence of diarrhea. cramping is loperamide, an opioid-receptoragonist that slows peristalsis. As such, it is not directed to relieve cramping from SUMMARY spasms, perse. Moreover, loperamide crosses the blood-brain 0009. The teachings provided herein relate to methods of barrier and, although quickly removed from the CNS by treating gastrointestinal spasms. The teachings include meth P-glycoprotein, it can be addictive if taken with a drug that ods of treating gastrointestinal spasms without having to use inhibits P-glycoprotein. Moreover, loperamide has several systemic drugs that have shown to (i) provide slow relief, (ii) contraindications, such that it’s not recommended for use cause adverse side effects, (iii) limit activities, (iv) worsen with several conditions that can include gastrointestinal existing gastrointestinal conditions, (v) be unrecommended spasms. For example, it is not recommended for treatment in several gastrointestinal conditions that include gastrointes with conditions containing organisms that cross the intestinal tinal spasms, or (vi) be unrecommended in the absence of walls, such as such as E. coli O157:H7 or salmonella. And, diarrhea. ironically, although it is often administered to alleviate 0010. In some embodiments, the teachings are directed to abdominal pain and cramping, its adverse effects can actually a method of treating a gastrointestinal spasm in a subject, the include abdominal pain and bloating, nausea, vomiting and method comprising administering an effective amount of a constipation. In fact, loperamide has been labeled as (i) con composition to a Subject having a gastrointestinal spasm, the traindicated in patients with abdominal pain in the absence of composition having a polyphenol combined with a reactive diarrhea; (ii) not recommended in children below 24 months oxygen species. And, in some embodiments, the composition of age; and (iii) not recommended as the primary therapy in can be produced from a process including combining a patients with (a) acute dysentery, which is characterized by polyphenol with a reactive oxygen species; selecting a blood in stools and high fever; (b) acute ulcerative colitis; (c) desired concentration for the composition; and, diluting the bacterial enterocolitis caused by invasive organisms includ composition to the desired concentration for the administer ing Salmonella, Shigella, and Campylobacter; or, (d) ing. In these embodiments, the polyphenol can have a pseudomembranous colitis associated with the use of broad molecular weight ranging from about 170 Daltons to about spectrum antibiotics. See, for example, http://dailymed.nlm. 4000 Daltons; and, the composition can relieve a gastrointes nih.gov/daily med/archives/fdal DrugInfo.cfm?ar tinal spasm in the Subject either (i) when compared to a chiveid=41053, Lake Erie Medical DBA Quality Care second Subject in a control group in which the composition Products LLC. was not administered or (ii) when compared to a historic US 2014/03701 18 A1 Dec. 18, 2014

baseline of the symptoms present in the Subject. The mea DETAILED DESCRIPTION Surement of relief from gastrointestinal spasms can be mea 0017 Methods of treating gastrointestinal spasms are pro Sured using any of a variety of parameters, in some embodi vided herein. The methods include treating gastrointestinal ments. For example, the relief of the spasm can be measured spasms without having to use systemic drugs. Such systemic using a response selected from the group consisting of a drugs have been reported to (i) provide slow relief, (ii) cause reduction in abdominal pain, a reduction in bloating, a reduc adverse side effects, (iii) limit activities, (iv) worsen existing tion inforceful defecation, a reduction inforceful vomiting, a gastrointestinal conditions, (v) be unrecommended in several reduction in defecation urgency, a reduction in constipation, gastrointestinal conditions that include gastrointestinal and/or a reduction in incontinence. spasms, or (vi) be unrecommended in the absence of diarrhea. 0.011 The polyphenol can comprise a single component, a 0018. In some embodiments, the method of treating a gas mixture of components, or a whole extract of a plant tissue, in trointestinal spasm in a subject comprises administering an Some embodiments. In some embodiments, the polyphenol effective amount of a composition to a subject having a gas comprises a tannin. In some embodiments, the polyphenol trointestinal spasm, the composition having a polyphenol comprises a hydrolysable tannin, a condensed tannin, or a combined with a reactive oxygen species. And, in some combination of a hydrolysable tannin and a condensed tannin. embodiments, the composition can be produced from a pro In some embodiments, the polyphenol can comprise a cess including combining a polyphenol with a reactive oxy pseudotannin selected, for example, from the group consist gen species; selecting a desired concentration for the compo ing of gallic acid, which can be found in an extract of a sition; and, diluting the composition to the desired rhubarb plant tissue, for example; flavan-3-ols or catechins, concentration for the administering. In these embodiments, which can be found in an extract of acacia, catechu, cocoa, or the polyphenol can have a molecular weight ranging from guarana, for example; chlorogenic acid, which can be found about 170 Daltons to about 4000 Daltons; and, the composi in coffee, or mate; or, ipecacuanhic acid, which can be found tion can relieve a gastrointestinal spasm in the Subject either in carapichea ipecacuanha, for example. As such, it should be (i) when compared to a second Subject in a control group in appreciated that, in Some embodiments, the polyphenol com which the composition was not administered or (ii) when ponent can comprise a flavanol or a catechin. Moreover, the compared to a historic baseline of the symptoms present in the polyphenol can comprises gallic acid, epigallic acid, or a Subject. combination thereof, in Some embodiments. 0019. To provide a desired therapeutic relief, the compo 0012. The reactive oxygen species can be any such species sitions can be directed to act on tissues at a particular target known to one of skill to have the ability to combine with the site, which can be gastrointestinal tissue, in some embodi polyphenol as a composition for the uses taught herein. In ments. The term “target site' can be used to refer to a select Some embodiments, the reactive oxygen species comprises location at which the composition acts to provide a therapeu hydrogen peroxide. And, in some embodiments, the hydro tic effect, or treatment as described herein. In some embodi gen peroxide can be combined with the tannin at a tannin: ments, the target site can be a tissue of any organ in which peroxide weight ratio that ranges from about 1:1000 to about control of a spasm is desirable. Moreover, the target can 10:1. In some embodiments, the weight ratio of the tannin: include any site of action in which the phenolic compound peroxide ranges from about 1:1 to about 1:50. can be site-activated by an oxidoreductase enzyme that is available at the site. The oxidoreductase enzyme can be pro 0013 And, consistent with the above, one of skill will duced endogeneously by a tissue at a target site, produced appreciate that the polyphenol can be combined with the endogeneously by a microbe, introduced exogenously to the reactive oxygen species as a component of a water or alcohol target site, include more than one enzyme, co-enzyme, cata extract of a plant tissue. In some embodiments, the plant lyst, or cofactor, or a combination thereof. The measurement tissue can comprise a tannin or a pseudotannin. of relief from gastrointestinal spasms, for example, can be 0014. One of skill reading the teachings that follow will measured using any of a variety of parameters. For example, appreciate that the concepts can extend into additional the relief of the spasm can be measured using a response embodiments that go well-beyond a literal reading of the selected from the group consisting of a reduction in abdomi claims, the inventions recited by the claims, and the terms nal pain, a reduction in bloating, a reduction in forceful def recited in the claims. ecation, a reduction in forceful vomiting, a reduction in def ecation urgency, a reduction in constipation, and/or a reduction in incontinence. BRIEF DESCRIPTION OF THE FIGURES 0020. Without intending to be bound by any theory or mechanism of action, the compositions taught herein can 0015 FIGS. 1A-1H are photographs of the dry forms of include phenolics, for example, polyphenols. The phenolic (A) gallic acid (a model polyphenol building block) bound to compounds taught herein are selected to combine with a hydrogen peroxide; (B) gallic acid alone; (C) tannic acid (a reactive oxygen species to form a composition that is deliv model polyphenol) bound to hydrogen peroxide: (D) tannic erable as a stable, or Substantially stable, system. In some acid alone; (E) pomegranate husk extract bound to hydrogen embodiments, the compositions can include a polyphenol peroxide; (F) pomegranate husk extract alone; (G) green tea component combined with hydrogen peroxide, a combina extract bound to hydrogen peroxide; and (H) green tea extract tion of components having an association that offers a stabil alone, according to some embodiments. ity and activity, both of which are offered by neither compo 0016 FIGS. 2A and 2B show that the stability of the nent alone. Such a composition can be delivered to a target hydrogen peroxide in the combination is consistently, Sub site, for example, in a polar solution Such as water or an stantially greater in an aqueous Solution than the stability of alcohol. In some embodiments, at least a Substantial amount the hydrogen peroxide alone in the aqueous Solution, accord of the hydrogen peroxide can remain bound, or otherwise ing to Some embodiments. associated with, and thus stable or substantially stable, with US 2014/03701 18 A1 Dec. 18, 2014 the phenolic compound. Moreover, in some embodiments, reactive oxygen species loses greater than about 12%, about the composition contains no, or Substantially no, unbound 15%, about 25%, about 35%, about 45%, about 50%, about hydrogen peroxide. The teachings also include a pharmaceu 60%, or even about 70% of its original oxidation potential. tical formulation comprising the compositions taught herein The loss may be measured by measured by comparing its and a pharmaceutically acceptable excipient. oxidation potential after making the composition to the time 0021. The terms “composition.” “compound,” “binding of administration, and this can include areasonable shelflife, system.” “binding pair, and “system can be used inter in Some embodiments. The time to compare the oxidation changeably in Some embodiments and, it should be appreci potential for a measure of stability can range from about 30 ated that a “formulation' can comprise a composition, com minutes to about one hour, from about one hour to about 12 pound, binding system, binding pair, or system presented hours, from about 12 hours to about 1 day, from about one day herein. Likewise, in some embodiments, the compositions to about one week, from about 1 week to about 1 month, from taught herein can also be referred to as an "agent a “bioac about 1 month to about 3 months, from about 1 month to a tive agent, or a "supplement whether alone, in a pharma year, from 3 months to a year, from 3 months to 2 years, from ceutically acceptable composition or formulation, and 3 months to 3 years, greater than 3 months, greater than 6 whether in a liquid or dry form. Moreover, the term “bioac months, greater than one year, or any time or range of times tivity” can refer to a treatment that occurs through the use of therein, stated in increments of one hour. the compositions provided herein. One of skill will appreciate 0023. One of skill will appreciate that the phenolic com that the term “bind,” “binding” “bound,” “attached,” “con pound used in the compositions can be any phenolic com nected,” “chemically connected.” “chemically attached.” pound that functions consistent with the teachings provided “combined, or “associated can be used interchangeably, in herein, and there are at least several thousand Such phenolic Some embodiments. Such terms, for example, can be used to compounds known to those of skill that can be expected to refer to any association between the polyphenol and reactive function as desired. As such, the teachings provided herein oxygen species that has resulted in an increased Stability can only include examples of the general concepts rather than and/or Sustained activity of the composition or components in a comprehensive listing of all possibilities and permutations the compositions. For example, the terms can be used to of the systems that are enabled by the teachings. describe a chemical bonding mechanism known to one of 0024. The phenolic component can be a polyphenol, and skill, such as covalent, ionic, dipole-dipole interactions, Lon the polyphenol can comprise a single component, a mixture don dispersion forces, and hydrogen bonding, for example. In of components, or a whole extract of a plant tissue, in some Some embodiments, the compositions can comprise a phe embodiments. In some embodiments, the polyphenol com nolic compound sharing hydrogen bonds with a reactive oxy prises a tannin. In some embodiments, the polyphenol com gen species, for example, Such as hydrogen peroxide. In some prises a hydrolysable tannin, a condensed tannin, or a com embodiments, the phenolic compound can comprise a bination of a hydrolysable tannin and a condensed tannin. In polyphenol that covalently binds to an amino acid or polyol. Some embodiments, the polyphenol can comprise a pseudot 0022. One of skill will appreciate that the compositions annin selected, for example, from the group consisting of should remain stable, or at least substantially stable, until gallic acid, which can be found in an extract of a rhubarb plant useful or activated, and this can relate to a measure of time. tissue, for example; flavan-3-ols or catechins, which can be Such a measure of time can include a shelf life, or a time found in an extract of acacia, catechu, cocoa, or guarana, for between creation of the composition and administration of example, chlorogenic acid, which can be found in coffee, or the composition, or some combination thereof. In some mate; or, ipecacuanhic acid, which can be found in carapichea embodiments, the composition is stable, or Substantially ipecacuanha, for example. As such, it should be appreciated stable, when usable as intended within a reasonable amount that, in Some embodiments, the polyphenol component can of time. In some embodiments, the composition should be comprise a flavanol or a catechin. Moreover, the polyphenol usable within a reasonable time from the making of the com can comprises gallic acid, epigallic acid, or a combination position to the administration of the composition and, in some thereof, in some embodiments. embodiments, the composition should have a reasonable 0025. In some embodiments, the phenolic compound has commercial shelflife. The composition can be considered as at least one aryl group, or arene moiety, and at least two polar “stable' if it loses less than 10% of its original oxidation aromatic groups, such as aromatic hydroxyl groups. In some potential, and this can be measured by comparing its oxida embodiments, the polar aromatic groups can be, for example, tion potential after making the composition to the time of hydroxyl, amine, amide, acyl, carboxy, or carbonyl. In some administration, and this can include a reasonable shelflife, in embodiments, the phenolic compound has at least two aryl Some embodiments. In some embodiments, the composition groups, and at least two hydroxyl groups. In some embodi can be considered as stable if it loses less than 5%, 3%, 2%, or ments, the phenolic compounds can be naturally occurring, 1% of its original oxidation potential when comparing its Such as from a plant or other natural product. And, in some oxidation potential after making the composition to the time embodiments, the phenolic compounds can be synthetically of administration, and this can include areasonable shelflife, or semi-synthetically produced. The compounds can be in some embodiments. The composition can be considered as simple monomers, oligomers, or polymers. The polymers can “substantially stable' if it loses greater than about 10% of its be in the class of polyphenols or polymeric phenols, where original oxidation potential, as long as the composition can one of skill will understand that the general difference is perform its intended use to a reasonable degree of efficacy. typically that polyphenols generally do not have a repeating The loss can be measured, as above, by measured by compar unit, whereas polymeric phenols do. There are exceptions, ing its oxidation potential after making the composition to however, such that groups of polyphenols and polymeric the time of administration, and this can include a reasonable phenols can overlap. In most embodiments, the phenolic shelf life, in some embodiments. In some embodiments, the compound used in the binding system can be any phenolic composition can be considered as Substantially stable if a compound taught herein, or any prodrugs, codrugs, metabo US 2014/03701 18 A1 Dec. 18, 2014 lites, analogs, homologues, congeners, derivatives, salts, Sol colloidal foams, colloidal dispersions, or hydrosols. In some Vates, and combinations thereof. embodiments, the liquid formulation can include particles 0026. In some embodiments, the phenolic compounds having sizes ranging, for example, from about 5 nm to about bind to hydrogen peroxide to form a binding pair and, in some 200 nm, from about 5 nm to about 500 nm, from about 5 nm. embodiments, the binding pair remains stable, or substantial to about 750 nm, from about 50 nm to about 1 um. In some stable in water. In some embodiments, the binding pair embodiments, the liquid formulations can be suspensions, in remains stable, or Substantial stable in an alcohol. And, in which the particle size range from about 1 um to about 10um, Some embodiments, the binding pair remains stable, or Sub from about 1 um to about 7 um, from about 1 um to about 5 stantial stable, in a polar solvent Such as, for example, a saline um, or any range therein. In some embodiments, the liquid Solution, an aqueous emulsion, a hydrogel, and the like. formulation can include particles having sizes ranging from 0027. In some embodiments, the phenolic compounds are about 1 nm to about 10 um. polyphenols having molecular weights ranging from about 0030 The functionality of a phenolic compound in the 170 to about 4000 Daltons, having from about 12 to about 16 teachings herein can, for at least the reason of Solubility, phenolic hydroxyl groups, and having from about five to depend on molecular weight, alone or in addition to other about seven aromatic rings, for every about 1000 Daltons in factors discussed herein Such as, for example, extent of molecular weight. In some embodiments, the phenolic com hydroxylation, presence and location of ketone or quinine pounds function to precipitate alkaloids and proteins. In some groups, and the presence of other functional groups. In some embodiments, the phenolic compounds can bind to cellular embodiments, the molecular weights of the phenolic com receptors, amino acids, peptides, oligopeptides, polyols, sac pounds can range from about 110 Daltons to about 40,000 charides, or combinations thereof. In some embodiments, the Daltons. In some embodiments, the molecular weights of the phenolic compounds have at least from about 1 to about 20 phenolic compounds can range from about 200 Daltons to polyhydroxylated phenolic units and have at least moderate about 20,000 Daltons, from about 300 Daltons to about water solubility. 30,000 Daltons, from about 400 Daltons to about 40,000 0028. The term “solubility’ can refer to a concentration of Daltons, from about 500 Daltons to about 10,000 Daltons, a solute in a solvent, for example, the phenolic compound in from about 1000 Daltons to about 5,000 Daltons, from about water. The concentration can be expressed by mass, for 170 Daltons to about 4000 Daltons, from about 350 Daltons example, mg of the phenolic compound per kg of water at to about 4,000 Daltons, from about 300 Daltons to about ambient temperature and pressure. This ratio of mg/kg can be 3,000 Daltons, from about 110 Daltons to about 2,000 Dal used interchangeably with ppm, and ng/kg can be used inter tons, from about 200 to about 5000 Daltons, or any range or changeably with ppb. In some embodiments, the solubility of molecular weight therein in increments of 10 Daltons. the phenolic compound can be higher than about 500,000 0031. In some embodiments, the ratio of aromatic rings to ppm or less than about 1 ppm. In some embodiments, the molecular weight of the phenolic compounds can range from solubility of the phenolic compound range from about 10 ppb about five to about seven aromatic rings for every about 1000 to about 500,000 ppm, from about 100 ppb to about 250,000 Daltons. In some embodiments, the ratio of aromatic rings to ppm, from about 1 ppm to about 100,000 ppm, from about 10 molecular weight of the phenolic compounds can range from ppm to about 50,000 ppm, from about 50 ppm to about 25,000 about 2 to about 10 aromatic rings for every about 1000 ppm, from about 100 ppm to about 10,000 ppm, from about Daltons, from about 3 to about 9 aromatic rings for every 100 ppm to about 100,000 ppm, from about 200 ppm to about about 1000 Daltons, from about 4 to about 8 aromatic rings 100,000 ppm, from about 250 ppm to about 50,000 ppm, from for every about 1000 Daltons, from about 5 to about 7 aro about 500 ppm to about 25,000 ppm from about 250 ppm to matic rings for every about 1000 Daltons, from about 1 to about 10,000 ppm, or any range therein. In some embodi about 5 for every about 500 Daltons, from about 1 to about 4 ments, the solubility can range from about 1 g/L to about for every about 500 Daltons, from about 1 to about 3 for every 10,000 g/L, from about 5 g/L to about 5000 g/L, from about about 500 Daltons, from about 2 to about 4 for every about 10 g/L to about 3000 g/L, from about 20 g/L to about 2000 500 Daltons, or any amount or range therein in increments of g/L, from about 50 g/L to about 1000, g/L, from about 100 g/L 1 ring. to about 500 g/L, or any range therein. For purposes of the 0032. One of skill will appreciate that, in some embodi teachings provided herein, a compound can be considered to ments the phenolic compounds can have, or be synthesized or have a low solubility if the solubility is less than about 50 g/L, otherwise designed to contain functional groups that are a moderate solubility if the solubility ranges from about 50 capable of releasably bonding to a reactive oxygen species, in g/L to about 1000 g/L, and a high solubility if the solubility is a stable or substantially stable form, until either consumed or above about 1000 g/L. In some embodiments, the phenolic released upon bioactivation at a target site. In some embodi compound can have a low solubility. In some embodiments, ments, a releasable bond can include any bond other than a the phenolic compound can have a moderate Solubility. And, covalent bond. In some embodiments, a releasable bond is a in Some embodiments, the phenolic compound can have a hydrogen bond. As such, the phenolic compounds should be high solubility. capable of forming, for example, a hydrogen bond with a 0029. One of skill will appreciate that the phenolic com reactive oxygen species upon Such bioactivation. In some pounds can still be useful at low solubilities in cases where the embodiments, the phenolic compound shares hydrogen solubility is too low to form a true solution. In some embodi bonding with hydrogen peroxide and is released through a ments the phenolic compounds can be ground into particles to bioactivation that occurs when the binding pair comes into form a colloidal mixture or suspension that will function contact with an oxidoreductase enzyme or other reducing consistent with the teachings provided herein. As such, liquid agent. In some embodiments, the phenolic compound can formulations include colloids and Suspensions in some have functional groups that comprise acyl, amido, amino, embodiments. The formulations can be a dispersed phase carbonyl, carboxyl, hydroxyl, or peroxyl functionality. In mixture in the form of colloidal aerosols, colloidal emulsions, some embodiments, the hydrogen bond between the reactive US 2014/03701 18 A1 Dec. 18, 2014 oxygen species and the phenolic compound can include any they can range from monophenols to oligophenols. In some hydrogen donor and any hydrogen acceptor having an avail embodiments, the natural phenols are found in plants, have an able lone pair of electrons. In some embodiments, the hydro antioxidant activity, or a combination thereof. Examples of gen acceptor can include, for example a N, O, or Fatom, or a the natural phenols include, for example, catechol- and resor combination thereof. In some embodiments, the phenolic cinol-types (benzenediols) with two phenolic hydroxy compound can have Such a functionality, can be derivatized to groups, and pyrogallol- and phloroglucinol-types (benzen have such a functionality, can be linked to another compound etriols) with three hydroxy groups. Natural phenols may have having Such a functionality, can be placed in a carrier having heteroatom Substituents other than hydroxyl groups, ether Such a functionality, or some combination thereof. and ester linkages, carboxylic acid derivatives, or some com 0033. In some embodiments, phenolic compounds can bination thereof. In some embodiments, the natural phenols include simple phenols, such as those containing 6 carbons, a include natural phenol drugs and their derivatives. Examples C6 structure, and 1 phenolic cycle. Such as the benzene alco of Such drugs include, but are not limited to, anthraquinone hols, examples of which include phenol, benzene diols and drugs, flavone drugs, and flavonol drugs. Examples of its isomers such as catechol, and the benzenetriols. In some anthraquinone drugs include, but are not limited to, aloe embodiments, phenolic compounds can include phenolic emodin, aquayamycin, and diacerein. Examples of flavone acids and aldehydes, such as those containing 7 carbons, a drugs include, but are not limited to, ansoxetine and C6-C1 structure, and 1 phenolic cycle, examples of which hidrosmin. Examples of flavonol drugs include, but are not include gallic acid and salicylic acids. In some embodiments, limited to, monoxerutin and troXerutin. phenolic compounds can include, for example, tyrosine 0035. In some embodiments, the phenolic compound is a derivatives, and phenylacetic acids, such as those containing tannin, a polyphenolic phenylpropanoid, or a combination 8 carbons, a C6-C2 structure, and 1 phenolic cycle, examples thereof. In some embodiments, the tannin is a hydrolysable of which include 3-acetyl-6-methoxybenzaldehyde, tyrosol, tannin, a condensed tannin, or a combination thereof. and p-hydroxyphenylacetic acid. In some embodiments, phe Hydrolysable tannins can be found, for example, in chinese nolic compounds can include hydroxycinnamic acids, phe gall, which is almost pure in that it has no or Substantially no nylpropenes, chromones, such as those containing 9 carbons, condensed tannins. Condensed tannins can be found, for a C6-C3 structure, and 1 phenolic cycle, examples of which example, in green tea leaf, which is also almost pure in that it include caffeic acid, ferulic acids, myristicin, eugenol, has no or Substantially no hydrolysable tannins. umbelliferone, aesculetin, bergenon, and eugenin. In some 0036) Examples of hydrolysable tannin can include gallo embodiments, phenolic compounds can include naphtho tannic acids, quercitannic acids, ellagitannins, gallotannin, quinones, such as those containing 10 carbons, a C6-C4 struc pentagalloyl glucose, galloylquinic acid, galloyl-shikimic ture, and 1 phenolic cycle, examples of which include juglone acid, and punicalagin. In some embodiments, the hydrolys and plumbagin. In some embodiments, phenolic compounds able tannin is a gallotannin or elagitannin, and isomers can include Xanthonoids, Such as those containing 13 car thereof. Such as isomers that can precipitate protein. bons, a C6-C1-C6 structure, and 2 phenolic cycles, examples Examples of gallotannins include the gallic acid esters of of which include mangiferin. In some embodiments, phenolic glucose in tannic acid (C7HsO4) and pentagalloyl glucose compounds can include stilbenoids, and anthraquinones, (PGG), and isomers thereof, such as the isomers of PGG that Such as those containing 14 carbons, a C6-C2-C6 structure, function to precipitate proteins. Examples of an ellagitannin and 2 phenolic cycles, examples of which include resveratrol include castalin and punicalagin. In some embodiments, the and emodin. In some embodiments, phenolic compounds can tannin is a gallic acid ester having a molecular weight ranging include chalconoids, flavonoids, isoflavonoids, and neofla from about 500 Daltons to about 3000 Daltons. In some vonoids, such as those containing 15 carbons, a C6-C3-C6 embodiments, the tannin is a proanthocyanidin having a structure, and 2 phenolic cycles, examples of which include molecular weight of up to about 20,000 Daltons. In some quercetin, myricetin, luteolin, cyanidin, and genistein. In embodiments, the hydrolysable tannins are derivatives of gal Some embodiments, phenolic compounds can include lignans lic acid and characterized by a glucose, quinic acid or and neolignans, such as those containing 18 carbons, a shikimic acid core with its hydroxyl groups partially or totally C6-C3-C6 structure, and 2 phenolic cycles, examples of esterified with gallic acid or elagic acid groups. The com which include pinoresinol and eusiderin. In some embodi pounds can have 3 to 12 galloyl residues but may be further ments, phenolic compounds can include biflavonoids, such as oxidatively crosslinked and complex. Hydrolysable tannins those containing 30 carbons, a (C6-C3-C6) structure, and 4 can be readily synthesized, for example, to obtain a phenolic phenolic cycles, examples of which include amentoflavone. compound with a high number of polar functional groups that In some embodiments, phenolic compounds can include form multiple, stable hydrogen bonds between the tannin and polyphenols, polyphenolic proteins, lignins, and catechol hydrogen peroxide in the binding system. melanins, such as those containing >30 carbons. In these 0037. It should be appreciated that, while hydrolysable embodiments, the phenolic compounds can have, for tannins and most condensed tannins are water Soluble, some example, a (C6-C3), structure, a (C6), structure, a (C6-C3 very large condensed tannins are insoluble. In some embodi C6), structure, or some combination thereof, as well as ments, the phenolic compound can comprise a hydrolysable greater than about 12 phenolic cycles. Examples of Such tannin Such as, for example, burkinabin C, castalagin, casta embodiments can include, for example, the flavolans, in the lin, casuarictin, chebulagic acid, chebulinic acid, corilagin, class of condensed tannins. digallic acid, elagitannin, gallagic acid, gallotannin, 0034. In some embodiments, the phenolic compounds are glucogallin, grandinin, hexahydroxydiphenic acid, pentagal natural phenols that can be enzymatically polymerized. loyl glucose, punicalagin alpha, punicalagins, raspberry ella Derivatives of natural phenols can also be used in some gitannin, roburin A, Stenophyllanin A, Stenophyllanin A, tan embodiments. These embodiments can include phenolic nate, tannic acid, tellimagrandin II, terflavin B, or 3,4,5-tri compounds having less than 12 phenolic groups, such that O-galloylquinic acid. US 2014/03701 18 A1 Dec. 18, 2014

0038. In some embodiments, the phenolic compound can 0044. In some embodiments, the phenolic compound can be a flavonoid which includes several thousand natural phenol be selected from the group of phenolic acids and their esters compounds. Examples of the flavonoids include the fla consisting of chicoric acid (another caffeic acid derivative, is Vonols, flavones, flavan-3ol (catechins), flavanones, antho found only in the medicinal herb echinacea purpurea), chlo cyanidins, isoflavonoids, and hybrids of any combination of rogenic acid (found in high concentration in coffee (more these compounds. In some embodiments, the phenolic com concentrated in robusta than arabica beans, blueberries and pounds are the hydrolysable tannins such as, for example, tomatoes, and produced from esterification of caffeic acid), gallic acid. In some embodiments, the phenolic compounds cinnamic acid and its derivatives, such as ferulic acid (found are the lignins such as, for example, cinnamic acid. In some in seeds of plants such as in brown rice, whole wheat and oats, embodiments, the phenolic units can be dimerized or further as well as in coffee, apple, artichoke, peanut, orange and polymerized to formany of a variety of hybrids. For example, pineapple), ellagic acid (found in high concentration in rasp ellagic acid is a dimer of gallic acid and forms the class of berry and strawberry, and in ester form in red wine tannins), ellagitannins, or a catechin and a gallocatechin can combine ellagitannins (hydrolysable tannin polymer formed when to form theaflavin or the large class of thearubigins found in ellagic acid, a polyphenol monomer, esterifies and binds with tea. In another example, a flavonoid and alignan can combine the hydroxyl group of a polyol carbohydrate Such as glucose), to form a hybrid. Such a flavonolignans. gallic acid (found in gallnuts, Sumac, witch hazel, tea leaves, 0039. In some embodiments, the phenolic compound can oak bark, and many other plants), gallotannins (hydrolysable be a flavan-3ol. Examples include the catechins and the cat tannin polymer formed when gallic acid, a polyphenol mono echin gallates, where the catechin gallates are gallic acid mer, esterifies and binds with the hydroxyl group of a polyol esters of the catechins. In some embodiments, the phenolic carbohydrate such as glucose), rosmarinic acid (found in high compound is a catechin or epicatechin compound (the cis- or concentration in rosemary, oregano, lemon balm, sage, and trans- isomers). In some embodiments, the phenolic com marjoram), and salicylic acid (found in most vegetables, pound is (-)-epicatechin or (+)-catechin. In some embodi fruits, and herbs; but most abundantly in the bark of willow ments, the phenolic compound is epigallocatechin (EGC) or trees, from where it was extracted for use in the early manu gallocatechin (EC). In some embodiments, the phenolic com facture of aspirin). pound is a catechin gallate. Such as epigallocatechin gallate 0045. In some embodiments, the phenolic compound can (EGCG) be selected from the group of nonflavonoid phenolics con sisting of curcumin (has low bioavailability, because, much of 0040. In some embodiments, the phenolic compound can it is excreted through glucuronidation, but bioavailability can be selected from the group of flavones consisting of apigenin, be substantially enhanced by solubilization in a lipid (oil or luteolin, tangeritin, flavonols, isorhamnetin, kaempferol, lecithin), heat, addition of piperine, or through nanoparticu myricetin (e.g., extractable from walnuts), proanthocyanidins larization, flavonolignans, for example, silymarin which is a or condensed tannins, and quercetin and related phenolic mixture of flavonolignans extracted from milk thistle), compounds, such as rutin. eugenol and Xanthones (mangosteen, for example, is pur 0041. In some embodiments, the phenolic compound can ported to contain a large variety of Xanthones, some of which, be selected from the group of flavanones consisting of eriod like mangostin are believed to be present only in the inedible ictyol. hesperetin (metabolizes to hesperidin), and maringenin shell). (metabolized from naringin). 0046. In some embodiments, the phenolic compound can 0042. In some embodiments, the phenolic compound can have a low molecular weight (less than about 400 Daltons), be selected from the group of flavanols consisting of catechin, selected from the group consisting of caffeic acid, gentisic gallocatechin and their corresponding gallate esters, epicat acid, protocatechuic acid, phenylacetic acid, gallic acid, phlo echin, epigallocatechin and their corresponding gallate roglucinol carboxylic acid, and derivatives thereof. Such esters, theaflavin and its gallate esters, thearubigins, isofla compounds can form a sufficiently soluble binding pair, and Vone phytoestrogens (found primarily in Soy, peanuts, and their relatively high hydroxyl group to molecular weight ratio other members of the Fabaceae family), daidzein, genistein, creates favorable conditions for obtaining the intermolecular glycitein, stilbenoids, resveratrol (found in the skins of dark hydrogen bonds desired for the binding systems. colored grapes, and concentrated in red wine), pterostilbene 0047. In some embodiments, the phenolic compounds can (methoxylated analogue of resveratrol, abundant in Vac be from a natural extract, Such as an extract of a plant or other cinium berries), anthocyanins, cyanidin, delphinidin, malvi natural product. See, for example, U.S. Published Patent din, pelargonidin, peonidin, and petunidin. And, In some Application Nos. 20100158885 and 20110070198, each of embodiments, the phenolic compound can be ubiquinol an which is hereby incorporated by reference herein in its electron-rich (reduced) form of coenzyme Q10. entirety. Those skilled in the art of such extracts will under 0043. In some embodiments, the phenolic compound can stand that extracts of plant materials are not typically pure in be selected from the group of carotenoid terpenoid consisting one type of phenolic compound. Plant tannin extracts, for of alpha-carotene, astaxanthin (found naturally in red algae example, typically comprise heterogenous mixtures and and animals higher in the marine food chain, a red pigment derivatives of the above classes. familiarly recognized in crustacean shells and salmon flesh/ 0048 One of skill will appreciate, given the teachings roe), beta-carotene (found in high concentrations in butternut provided herein, that the polyphenol can be combined with squash, carrots, orange bell peppers, pumpkins, and Sweet the reactive oxygen species as a component of a water or potatoes), canthaxanthin, lutein (found in high concentration alcohol extract of a plant tissue. In some embodiments, the in spinach, kiwifruit and red peppers), lycopene (found in plant tissue can comprise a tannin or a pseudotannin. In some high concentration in ripe red tomatoes and watermelons) and embodiments, the phenolic compound is extracted from a Zeaxanthin (the main pigment found in yellow corn, also whole or partial plant tissue selected from the group consist abundant in kiwifruit). ing of seeds and fruits; ovaries; juice; pulp; galls; husks; bark; US 2014/03701 18 A1 Dec. 18, 2014

stems; leaves; flowers; sheaths; hulls; Sprouts; bulbs; hips: adducts of hydrogen peroxide Such as carbamide peroxide, tubers; roots of grains; grasses; legumes; trees; vegetables; magnesium peroxide, and sodium percarbonate; amino per medicinal herbs; tea leaves; algaes; marine plants; and, for hydrates; Superoxide dismutase decomposition of oZone, ages. One of skill will appreciate that the type and content of Superoxides or Superoxide salts; glucose oxidase and glucose, phenolic compound obtained can be expected to vary with the aqueous dilution of honey; H2O production by lactobacillus; species, season, geographical location, cultivation, and stor catalytic quinone hydrogenation; Superoxides; and, SuperoX age. Examples of plant tissues include, but are not limited to, ide dismutase. In some embodiments, the reactive oxygen plant tissues from the species of Aloe, Pachycereus, and species can include peroxide ion, organic peroxides, organic Opuntia. Other examples can include, but are not limited to, hydroperoxides, peracid Superoxides, dioxygenyls, oZones, Agavaceae, Cactaceae, Poaceae. Theaceae, Leguminosae, and oZonides. hydrogen peroxide or materials that generate and Lythraceae. In some embodiments, the plant tissues can hydrogen peroxide can be obtained orderived synthetically or be selected from the group consisting of pomegranate husk, from plant tissues or combinations of plant tissues. aloe vera leaves, and green tea leaves. Other examples of 0.052 Enzymes can activate the compositions for the plant tissues can include, but are not limited to Aloe (Aloe methods taught herein, and the systems for the methods of vera), Angelica (Angelica archangelica), Barberry (Berberis treatment can be designed accordingly. And, generally speak vulgaris) Root Bark, Bilberry (Vaccinium myrtillus), Calen ing, one of skill will appreciate that there area wide variety of dula (Calendula officinalis), Cramp bark (Viburnum opulus), enzymes are possible and can be target site dependent. Gen Eleutherococcus root (Eleutherococcus senticosus), Kidney erally, the enzymes fall into the classes of oxidoreductases. As wood (Eysenhardtia Orththocarpa), Mimosa tenuiflora, Such, there are several enzymes and isozymes that will be Papaya (Carica papaya) leaves, Paul D'Arco (Tabebuia avel presentata target site and capable of bioactivating the binding lanedae), Sassafras albidum root bark, Saw Palmatto (Ser systems. In some embodiments, the oxidoreductases can be enoa repens), St John’s wort (Hypericum perforatum), Vale categorized into about 22 classes, and the selectivity of the rian (Valeriana officinalis), Apple (Malus domestica), Grape bioactivation of the binding system at a target site depends, at (Vitis vinifera), Echinacea purpurea, Grape seed extract, and least in part, on the selectivity of the oxidoreductase at the Blueberry (Vaccinium corymbosum). In some embodiments, target site. In some embodiments, the oxidoreductase can the plant tissues are selected from the group consisting of include those oxidoreductases that act on the CH-OH group barley germ, green tea leaves, aloe vera leaves, mung beans, of donors (alcohol oxidoreductases, for example: EC Number carrot, cereal grains, seeds, buds, and sprouts. class 1.1). In some embodiments, the oxidoreductase can 0049. Likewise, one of skill will appreciate that there are include those oxidoreductases that act on diphenols and numerous reactive oxygen species that can be used in the related Substances as donors (catechol oxidase, for example, systems taught herein, as long as the reactive oxygen species EC Number class 1.10). In some embodiments, the oxi function consistent with Such teachings. Hydrogen peroxide, doreductase can include those oxidoreductases that act on and precursors of hydrogen peroxide, are merely examples. In peroxide as an acceptor (peroxidases, such as horseradish Some embodiments, the phenolic compounds in the compo peroxidase and catalase; EC Number class 1.11). In some sitions (i) have phenolic hydroxyl groups that are oxidizable embodiments, the oxidoreductase can include those oxi in the presence of a reactive oxygen species and an oxi doreductases that act on phenols as an acceptor (tyrosinases, doreductase enzyme, and (ii) are soluble in a polar liquid, for example: EC Number class 1.14). Examples of other Such as water or an alcohol, for example, or at least moder useful enzymes for the teachings provided herein include, but ately soluble. The phenolic compounds should also be (iii) are not limited to, glutathione peroxidase 1 and 4 (in many non-toxic to a subject upon administration. And, in some mammalian tissues), glutathione peroxidase 2 (in intestinal embodiments, the phenolic compounds should also (iv) and extracellular mammalian tissues), glutathione peroxidase crosslink or polymerize with itself or other phenolic com 3 (in plasma mammalian tissues), lactoperoxidase, myelop pounds in the compositions taught herein. eroxidase (in salivary & mucosal mammalian tissues), 0050. The reactive oxygen species can be any such species myeloperoxidase (in neutrophil mammalian tissues), cyto known to one of skill to have the ability to combine with the chrome peroxidase (in yeasts such as Candida albicans) and polyphenol as a composition for the uses taught herein. For horseradish peroxidase (common to show in vitro activity). example, the reactive oxygen species can include, but is not One of skill will appreciate that oxidoreductases are selective limited to, the reactive oxygen species includes a component and, in Some embodiments, the oxidoreductase can include an selected from the group consisting of hydrogen peroxide, alternate enzyme that are selective for a binding system hav Superoxide anion, singlet oxygen, and a hydroxyl radical. In ing a phenolic compound that acts as a Substrate for the Some embodiments, the reactive oxygen species comprises alternative enzyme. hydrogen peroxide. And, in some embodiments, the hydro 0053. In some embodiments, the oxidoreductases include gen peroxide can be combined with the tannin at a tannin: mono-oxygenases such as, for example, phenylalaning peroxide weight ratio that ranges from about 1:1000 to about monooxygenase, tyrosine monooxygenase, and tryptophan 10:1. In some embodiments, the weight ratio of the tannin: monooxygenase. In some embodiments, the oxidoreductases peroxide ranges from about 1:1 to about 1:50. In some include dioxygenases such as, for example, tryptophan embodiments, the exogeneous reactive oxygen species can be dioxygenase, homogentisate dioxygenase, trimethyl lysine generated, as hydrogen peroxide for example, from a solid dioxygenase, and nitric oxide synthase. In some embodi hydrogen peroxide generating material selected from the ments, the oxidoreductases include peroxidases such as, for group consisting of sodium percarbonate, potassium percar example, catalase, myeloperoxidase, thyroperoxidase. In bonate, a carbamide peroxide, and urea peroxide. Some embodiments, the oxidoreductases act in the presence 0051. In some embodiments, the reactive oxygen species of a co-factor or co-enzyme, such as nicotinamide adenine is hydrogen peroxide or materials that release or generate dinucleotide phosphate (NADP) or nicotinamide adenine hydrogen peroxide including, but not limited to, hydration of dinucleotide (NAD). US 2014/03701 18 A1 Dec. 18, 2014

Methods of Making the Compositions oxide. In fact, higher concentrations are available, and could 0054 The design of the binding systems include (i) select be used in some embodiments if handled properly. One of ing the phenolic compound, (ii) selecting the reactive oxygen skill will be able to readily select, obtain and/or produce species, (iii) selecting the ratio of phenolic compound to desired concentrations of hydrogen peroxide. Again, one of reactive oxygen species, and (iv) selecting a carrier. In some skill can easily select the dose for a particular use, which will embodiments, the phenolic compound can be derivatized or vary according to factors that include environmental condi attached to another chemical moiety via a linker, or another tions at the site of use. In some embodiments, this formulation known method Such as, for example, esterification to facili has worked well for uses in animals that are non-humans. tate or improve an association between the phenolic com 0057 The compositions can include, for example, a pound and the reactive oxygen species, as well as to poten weight (molar or mass) ratio of phenolic compound to reac tially modify, Solubility, tissue absorption, or toxicity. tive oxygen species that ranges from about 1:1000 to about 0055 One of skill will appreciate that, at least from the 1000:1. In some embodiments, the ratio of phenolic com teachings provided herein, there are a vast number of com pound to reactive oxygen species can range from about ponents that can be selected, the selection of which is, at least 1:1000 to about 500:1, from about 1:500 to about 500:1, from in part, dependent on type of enzyme, co-enzymes, cofactors about 1:250 to about 500:1, from about 1:500 to about 250:1, or catalysts present at the target site for the bioactivation of from about 1:250 to about 250:1, from about 1:100 to about the system. The design of the system can include for example, 250:1, from about 1:250 to about 100:1, from about 1:100 to (i) identifying the target site; (ii) identifying an enzyme, co about 100:1, from about 1:100 to about 50:1, from about 1:50 enzymes, cofactors, or catalysts present at the target site but to about 100:1, from about 1:50 to about 50:1, from about not present at tissue Surrounding the target site; (iii) selecting 1:25 to about 50:1, from about 1:50 to about 25:1, from about a binding pair for activation at the target site by the enzyme, 1:25 to about 25:1, from about 1:10 to about 10:1, from about co-enzymes, cofactors, or catalysts; and, (iv) selecting a car 1:1000 to about 250:1, from about 1:1000 to about 100:1, rier in which the binding pair is stable or substantially stable. from about 1:1000 to about 50:1, from about 1:1000 to about Identifying the target site can include, for example, select a 25:1, from about 1:1000 to about 10:1, from about 1:1000 to target tissue for treatment, such as a spastic tissue at which the about 5:1, from about 1:10 to about 1:20, from about 1:10 to enzyme, co-enzymes, cofactors or catalysts present. In some about 1:30, from about 1:10 to about 1:40, from about 1:10 to embodiments, the target site is a GI tissue, at which peroxi about 1:50, from about 1:10 to about 1:60, from about 1:10 to dase or oxidase may be present. Identifying an enzyme, co about 1:70, from about 1:10 to about 1:80, from about 1:10 to enzymes, cofactors, or catalysts present at the target site but about 1:90, from about 1:20 to about 1:30, from about 1:20 to not present at tissue Surrounding the target site can include, about 1:40, from about 1:20 to about 1:50, from about 1:20 to for example, identifying the tissue type, as well as the pres about 1:60, from about 1:20 to about 1:70, from about 1:20 to ence of a microbe. Anaerobic pathogens such as Pseudomo about 1:80, from about 1:20 to about 1:90, from about 1:30 to nas and Vibrio, for example, can express a peroxide or an about 1:90, or any range therein. oxidase, making these enzymes available at the target site. 0058. In some embodiments, the composition comprises a 0056. After the system and environment of use are known, ratio of a tannin and hydrogen peroxide, a phenylpropanoid one of skill can select a carrier in which the composition is and a hydrogen peroxide, a catechin and hydrogen peroxide, stable or Substantially stable. In one example, the binding an epigallic acid and a hydrogen peroxide, or a combination system can comprise a mixture of phenolic compounds in a thereof an of these phenolic compounds with hydrogen per desired ratio with hydrogen peroxide. For example, the phe oxide. nolic compounds can include a mixture of a pomegranate 0059. In some embodiments, the compositions include a extract and a green tea extract, and the ratio of phenolic stable hydrogen bonded complex between the phenolic com compound to hydrogen peroxide can range from about 1:2 to pound and the reactive oxygen species. For example, a highly about 1:20 on a wit/wt basis, which can include molar weight hydroxylated polyphenol compound can be combined with a bases. In some embodiments, the hydrogen peroxide can be high concentration of hydrogen peroxide, the combination added to the phenolic compound using a concentration of leading to binding the hydrogen peroxide to the phenolic about 0.01% to about 10% hydrogen peroxide solution, and compound to produce the binding system. The binding sys any free hydrogen peroxide can remain or be removed using tem can be intended for dilution in water or a solid excipient. the teachings provided herein. One of skill can easily select One of skill will appreciate that such a complex can be the dose for a particular use, which will vary according to referred to as a polyphenol peroxySolvate, in some embodi factors that include the environmental conditions at the site of ments, when in a liquid form for storage or administration to use. In another example, the compositions can comprise a a subject, and a phenolic perhydrate when in an anhydrous, or mixture of phenolic compounds in a desired ratio with hydro Substantially anhydrous, form for storage or administration to gen peroxide. For example, the phenolic compounds can a Subject. include a mixture of a pomegranate extract and a green tea 0060. The compositions can be carried in a liquid, powder, extract, and the ratio of phenolic compound to hydrogen capsule, tablet, or gas for administration to a subject. The peroxide can range from about 3:1 to about 1:3 on a wit/wt selection of the phenolic compound should take into consid basis (e.g., molar weight). The hydrogen peroxide can be eration the manner in which the reactive oxygen species will added to the phenolic compound using a concentration of bind to the phenolic compound to form a stable, or Substan about 0.01% to about 10% hydrogen peroxide. In some tially stable, binding pair. The binding pair can be considered embodiments, a 35% hydrogen peroxide stock Solution can Substantially stable where the reactive oxygen species retains be used as a source of hydrogen peroxide, which can be all, most, or at least a predictable amount of oxidation obtained from a commercially available stock solution, for strength for the uses and functions recited herein. example. In some embodiments, up to 60% hydrogen peroX 0061. One of skill will appreciate that a phenolic com ide stock Solution can be used as a source of hydrogen per pound can be derivatized to introduce or enhance a desired US 2014/03701 18 A1 Dec. 18, 2014 function. The phenolic compound can be derivatized, for tissue, denature the endogeneous enzymes, and Soak the tis example, to increase it’s functionality for binding to the reac sue in water to isolate the water soluble extract of the plant tive oxygen species, maintaining stability or miscibility in a tissue. Another simple extraction method would be to harvest carrier, or binding to a target site, using any method known to the plant tissue, and isolate the water soluble extract of the one of skill. In some embodiments, the phenolic compound tissue in water at temperatures greater than about 80° C. to can be bound to a polyol, pegylated, attached to a saccharide, steam. An even simpler process would not include denaturing or attached to glucose, for example. the enzymes, but the stability and activity of the extract in the 0062 Moreover, one of skill will appreciate that the com composition Suffers greatly. Additional steps can be added, positions should, in some embodiments, be produced free of however, to increase the efficiency of the extraction, although compounds that can lead to degradation of the otherwise Such steps are not required. For example, the harvesting can stable, or Substantially stable, combinations. As such, in some include cutting into as large of pieces as practical to the size of embodiments, the compositions comprise Solutes that are the plant to preserve the metabolic activity in the plant tissue Substantially free of transition metals, metal ions, heavy met can be done. The plant tissue can be pulverized after denatur als, oxidoreductase enzymes, other strong oxidizers, reactive ing the enzymes, and the water can be heated attemperatures halogen compounds, hydrogen halides, and other compounds ranging from about 25°C. to about 100°C., from about 30°C. that can cause a decomposition of the reactive oxygen spe to about 95°C., from about 35° C. to about 90° C., from about cies, or its disassociation from the phenolic compound with 40° C. to about 85°C., from about 45° C. to about 80°C., from which it forms a binding pair. about 45° C. to about 75°C., from about 45° C. to about 70° 0063. The compositions can be made using ingredients C., from about 45° C. to about 65°C., or any amount or range from commercially available chemical providers, or they can therein in increments of 1°C., to make the process of extrac be made directly from whole, plant extracts, for example, tion more efficient. water extracts or alcohol extracts. 0072. In some embodiments, the endogeneous enzymes 0064 A Commercially Available Source of the Phenolic include a catalase or peroxidase that is at least Substantially Component inactivated. In some embodiments, the endogeneous 0065 Commercially available chemical providers, for enzymes can be inactivated through heating, cooling, boiling, example Sigma-Aldrich, can provide phenolic and polyphe freezing, dessicating, freezing and thawing cycles, blanching, nolic chemicals for use with the methods of treatment taught or a combination thereof. In some embodiments, the endoge herein. In the example set forth below, (i) gallic acid (a model neous enzymes can be inactivated using a process that polyphenol building block) is combined with hydrogen per includes allowing natural degradation over time, adding at oxide; and, (ii) tannic acid (a model polyphenol component) least 1% salt, radiating, or adding an exogeneous chemical is combined with hydrogen peroxide. Both gallic acid and enzymatic inhibitor. tannic acid are commercially available from Sigma-Aldrich. 0073. In some embodiments, the plant extract is produced One of skill will appreciate that a wide variety of polypheno from a process comprising: lics are commercially available. 0074 harvesting the plant tissue; at least partially inacti 0066. A Whole, Plant Extract as a Source of the Phenolic Vating an endogeneous enzyme; optionally reducing particle Component size of the plant tissue through cutting, avulsing, or pulveriz 0067. The method of obtaining the phenolic component, ing; creating the extracted component through a process that e.g., the polyphenol component, from a plant tissue can be includes combining the plant tissue with water or alcohol for produced using the following process: an effective time and at an effective temperature; optionally 0068 i. Harvest plant tissue comprising a polyphenol removing particles from the mixture; and, adding the reactive component, for example, the polyphenol comprising a oxygen species to the effective, or otherwise desired, amount. tannin. It is desirable to harvest while minimizing physi 0075. In some embodiments, the water soluble plant cal damage to the plant tissue. For example, whole leaf extract can then be optionally filtered, for example, using a extractions can be performed to avoid physical damage filter, for example a 5 um filter in some embodiments, and to the leaves, but it may be desirable to reduce the size of hydrogen peroxide can then be added to the filtered extract to the leaves by cutting them, for example, to increase the a concentration of 1% by weight of the total composition. In speed and yield of the extraction in some embodiments. Some embodiments, the hydrogen peroxide can be added to 0069 ii. Denaturing all, or substantially all, of the oxi the extract in an amount ranging from about 0.01% to about doreductase enzymes in the plant. This can be done 10% by weight of the total composition. Increasing the con through drying, for example, using heating in the range centration of hydrogen peroxide added has been observed to of about 60° C. to about 150° C., or a combination of increase the potency and Stability of the resulting composi Such heating and dessication. Alcohols can also be used tions. to denature the enzymes. 0076. After combining the reactive oxygen species with 0070 iii. Extracting the polyphenols from the plant tis the polyphenol component, the free reactive oxygen species Sue using a suitable solvent including, but not limited to, in the compositions can be left in the composition, or it can be water oran alcohol. Water extractions have been used in removed using an enzyme, catalyst, or reducing agent. In this this example. Since were afterwater soluble plant mate example, the reactive oxygen species is hydrogen peroxide, rials, a simple water extraction is sufficient to provide and the free hydrogen peroxide can be removed from the the plant extract containing polyphenols for the compo composition in a Subsequent step contacting the free hydro sitions. gen peroxide with a hydrogen peroxide degrading enzyme, 0071. The plant extraction procedures are simple, Such catalase; a catalyst Such as manganese dioxide, plati although they can be modified for efficiency in product yield num, iron, or copper; or, a reducing agent such as ferric and activity. Although inefficient, the simplest extraction pro chloride, copper Sulfate, or sodium hypochlorite. In some cedure, for example, would be to merely harvest the plant embodiments, the composition having the free hydrogen per US 2014/03701 18 A1 Dec. 18, 2014

oxide can be contacted with a metal catalyst or catalase bound storage and transport. In some embodiments, the binding to a solid non-soluble Substrate. In some embodiments, the systems, whether in liquid or dry form, can be combined with Solid Substrate can be a bead column or screen, for example. Vitamins, electrolytes, and/or other nutrients in either liquid Likewise, the catalysts and reducing agents can be used in a or dry form. The dry form of the binding system can be similar manner to remove the free hydrogen peroxide, or any manufactured using any drying process known to one of skill, other free reactive oxygen species. Such as solvent exchange, vacuum drying, critical point dry 0077. As such, the concentration of free reactive oxygen ing, heating, dessication, or a combination thereof. In some species, such as free hydrogen peroxide, remaining in the embodiments, the phenolic compound is dried as a single composition can range from about 0 to about 10% based on component. In some embodiments, the binding pair is total dry weight of the composition. Moreover, in some formed, and the binding pair is dried together. And, in some embodiments, the total hydrogen peroxide concentration can embodiments, the reactive oxygen species can be, indepen range from about 0.001% to about 1%, from about 0.001% to dently, in any dry form known to one of skill. Such as the dry about 0.1%, from about 0.01% to about 0.05%, from about forms taught herein. In embodiments having the reactive oxy 0.005% to about 5%, from about 0.007% to about 2%, from gen species in an independent dry form, the dry phenolic about 0.01% to about 5%, from about 0.05% to about 5%, compound and the dry reactive oxygen species can be com from about 0.1% to about 5%, from about 0.2% to about bined in a polar solvent, for example, to create the binding 4.5%, from about 0.3% to about 4%, from about 0.4% to pair prior to use. about 3.5%, from about 0.5% to about 3%, from about 0.6% to about 2.5%, from about 0.7% to about 2%, from about Methods of Using the Compositions 0.001% to about 1.5%, about 1%, or any amount or range I0081 Methods of treating gastrointestinal spasms are pro therein in increments of 0.001%. And, it should be appreci vided. This can include reducing or eliminating abdominal ated that the concentration of free hydrogen peroxide, for pain, bloating, forceful defecation, forceful vomiting, defeca example, can also be reduced, or further reduced, by dilution tion urgency, constipation, and/or incontinence. Causes of of the composition in various commercial formulations. gastrointestinal cramping can range from mild conditions to 0078 Moreover, precipitates of protein or other impurities serious conditions, such as food poisoning, constipation, gas can form at this point and can optionally be removed by troenteritis, viral infections, bacterial infections, lactose additional filtration, and we often filter after we allow the intolerance, excessive flatulence and bloating, indigestion, Solution to react for about an hour. Although not necessary, diverticulitis, autoimmune disease, intestinal inflammation additional reactive oxygen species can be added to ensure and even colorectal cancer, adhesions, and the like. In some complete Saturation of hydrogen peroxide on the binding sites embodiments, stress and/or dehydration can even trigger gas of the polyphenols in the extract. In this example, hydrogen trointestinal cramps, for example. peroxide was used as the reactive oxygen species, keeping 0082. The disorders treated can be self-induced. In some track of the total hydrogen peroxide concentration. embodiments, gastrointestinal spasms can be self-induced 007.9 The plant extract is combined with the reactive oxy through overindulging, such as through overeating and/or gen species, and the solution can be allowed to react for a overdrinking. In some embodiments, gastrointestinal spasms period of time ranging from about 10 minutes to about 72 can be due to deficiencies, such as deficiencies in nutrition or hours, in some embodiments, before diluting the composition hydration, for example. The compositions taught herein can to a desired concentration. In some embodiments, the solu be used in treating such conditions, either alone or in co tion can be allowed to react for a period of time ranging from administrations with nutritional therapy or rehydration thera about 1 minute to about 96 hours, from about 5 minutes to pies. The disorders might also be induced through environ about 48 hours, from about 10 minutes to about 36 hours, mental conditions, exercise, or Socioeconomic conditions. In from about 10 minutes to about 24 hours, from about 10 Some embodiments, the composition can be co-administered minutes to about 12 hours, from about 10 minutes to about 8 with at least one other nutritional and/or rehydrating agent for hours, or from about 10 minutes to about 1 hour, or any range aiding recovery from a health imbalance, or to maintain a therein in increments of 1 minute. In this example, the health balance. Examples of rehydrating agents can include, extracts were allowed to react with the hydrogen peroxide for but are not limited to, GATORADE and other electrolyte a minimum of 2 hours. The dilution can be desirable, for drinks, oral rehydration solutions (ORSs) generally, new oral example, (i) to control the concentration of the composition in rehydration solution (N-ORS), SEUROORAL PEDIAONE, Solution, and/or (ii) to accelerate degradation of the unbound and PEDIALYTE. Examples of nutritional supplements can reactive oxygen species to limit the composition to having no. include, but are not limited to, Zinc sulfate, salted rice water, or Substantially no, free reactive oxygen species. In this salted yogurt-based drinks, and vegetable or chicken Soup example, the hydrogen peroxide is more Susceptible to deg with salt. Such health imbalances can include, but is not radation when free in solution, and one of skill will appreciate limited to, dehydration, malnutrition, electrolyte imbalance, that the degradation will increase in rate when the composi Vitamin deficiency, food hyperSensitivities, stress induced tion is diluted. diarrhea, abdominal cramping, and alcohol hangover, or a 0080. In some embodiments, dry compositions are pro combination thereof. In some embodiments, the methods vided. For example, the system can be in the form of a powder, taught herein can further include the administration of oral pill, tablet, capsule, or as separate dry components for mixing rehydrating or nutritional agents such as sodium, potassium, into a liquid form. In these embodiments, both the phenolic dextrose, fructose, glucose, magnesium, Zinc, Selenium, Vita compound and the reactive oxygen species are in a dry form minA, Vitamin D. Vitamin C, dietary fiber, and combinations either before or after creation of the binding pair, and the thereof. The amounts and ratios of the agents to the compo binding system can be used in the dry form, or converted to a sition can be substantially varied to provide prophylaxis, liquid form, for any of the uses taught herein. The advantages therapy or maintenance of healthful balance. Ratios of the of the dry compositions can include, for example, the ease of compositions herein to the nutritional agents or rehydration US 2014/03701 18 A1 Dec. 18, 2014 agents can range, for example, from about 1:100 to about I0086. In some embodiments, the compositions taught 100:1, from about 1:50 to about 50:1, from about 1:40 to herein can be used to protect, maintain, improve, or restore a about 40:1, from about 1:30 to about 30:1, from about 1:20 to digestive health of a subject when administered orally in an about 20:1, from about 1:10 to about 10:1, from about 1:5 to effective amount. In some embodiments, the effectiveness about 5:1, from about 1:4 to about 4:1, from about 1:3 to about can be measured by comparing to a control group that did not 3:1, from about 1:2 to about 2:1, from about 1:1.5 to about receive the binding system. And, in some embodiments, the 1.5:1, about 1:1, or any range therein. The ratios can be based effectiveness can be measured according to a historical base on Volume: Volume, mass: Volume, Volume: mass, mass:mass, line for the subject being treated. The binding systems can be or molar:molar. It should be appreciated that the concentra used to prevent, inhibit, or ameliorate the symptoms associ tions of the compositions taught herein can be the same or ated with a loss of digestive tract homeostasis. In some different than the concentrations of the nutritional agents or embodiments, the binding systems can be used to prevent, rehydration agents. And, it should also be appreciated that the treat, ameliorate the symptoms of, or even cure, a chronic concentrations and ratios of concentrations can be subjective gastrointestinal condition. Such conditions can include, but to a particular administration, Such that they can be indepen are not limited to, hyperacidity, colitis, irritable bowel syn dently selected according to the condition treated, objective drome, crohn's disease, necrotic enteritis, functional colonic sought, desired effect, and/or personal preference. The com diseases, malabsorption, a peptic ulcer, gastro-esophageal binations can be administered under any regime taught herein reflux disease, ulcerative colitis, and diverticulitis. In some for the administration of an agent or combination of agents. embodiments, the binding systems can be used to reduce mucosal tissue inflammation, dysfunction, or damage. Such 0083. Irritable bowel syndrome (IBS) is a problem of par conditions can be induced, for example, by drug side effects, ticular interest and includes, for example, chronic or frequent chemotherapy, dysbiosis, radiation, changes in normal flora, gastrointestinal spasms. IBS is often diagnosed as a set of hyperimmunity, autoimmune reactions, immune deficien these symptoms, such as diarrhea, constipation, and bloating, cies, nervousness, allergies, chemical irritation, and stress. In in addition to, perhaps, a measured food sensitivity. The com Some embodiments, the binding systems can be administered positions taught herein, however, can generally be used for for selectively inhibiting the growth of gastrointestinal patho this and other medicinal purposes, as a health Supplement, or gens. It should be appreciated that there may be lesser inhi a nutritional composition. The compositions can provide a bition of non-pathogenic strains, particularly common probi therapeutic and/or prophylactic effect in the treatment of a otic bacteria such as bifidobacteria and lactobacilli. And, in condition in a subject, particularly in the treatment of a gas Some embodiments, administration of the binding systems trointestinal spasm. The targeted action of the binding sys can produce short term immune modulation effects as well as tems allows for the administration of surprisingly low effec potentially change the chronic expression of the activating tive doses of the phenolic compounds. As a result, the enzymes associated with some conditions with longer term compositions also improve safety by Substantially increasing use of the binding systems. the separation between an effective dose and any toxic/side effects. I0087. In some embodiments, the symptoms of a gas trointestinal condition can include, for example, diarrhea, I0084. The terms “treat,” “treating,” and “treatment” can be dehydration, malnutrition, constipation, nausea, and/or used interchangeably and refer to the administering or appli cramping. And, in some embodiments, the symptoms of a cation of the binding systems taught herein, including Such gastrointestinal condition can be temporary and include acid administration as a health or nutritional Supplement, and all irritation, indigestion, bloating, cramps, spasmodic peristal administrations directed to the prevention, inhibition, ame sis, diarrhea, and constipation. Administering the binding lioration of the symptoms, or cure of a condition taught systems for the treatment and/or management of gastrointes herein. The terms “disease.” “condition,” “disorder, and “ail tinal conditions can be considered a nutritional or health ment can be used interchangeably in some embodiments. Supplement, in Some embodiments. In some such embodi The term “subject' and “patient' can be used interchangeably ments, for example, the binding pair can be administered to and refer to an animal Such as a mammal including, but not prevent, inhibit, or ameliorate the effect, infectivity, and viru limited to, non-primates such as, for example, a cow, pig, lence of pathogens including bacteria, virus, fungi, yeast, horse, cat, dog, rat and mouse; and primates such as, for prions, protozoa and parasites in a Subject orally taking an example, a monkey or a human. As such, the terms "subject' effective amount of the supplement. and “patient can also be applied to non-human biologic I0088 As described herein, the binding systems can be applications including, but not limited to, Veterinary, com used in a method of treating acute diarrhea in a Subject. In panion animals, commercial livestock, aquaculture, and the Some embodiments, the methods comprise orally administer like. Many of the applications can include control environ ing an effective amount of a binding system taught herein to mental pathogens that are on or in plants, as well as places not the Subject. The binding system can prevent, inhibit, or ame necessarily in living hosts, such as those that are in water and liorate a symptom of acute diarrhea in the Subject when com water systems, for example, as well as soil, air, and food for pared to a second Subject in a control group in which the microbial control, alteration of Surface characteristics, or binding system was not administered. In some embodiments, anywhere that can benefit from a supply of a stable oxidizer the symptom is selected from the group consisting of a stool SOUC. score, heartburn, indigestion, urgency of defecation, nausea, 0085. In some embodiments, the composition includes (i) Vomiting, stomach pain, and bloating. a phenolic compound selected from the group consisting of I0089. As described herein, the binding systems can be condensed tannins, hydrolysable tannins, complex tannins, used in a method of treating irritable bowel syndrome in a phlorotannins, pSuedotannins, and derivatives thereof, and, Subject. In some embodiments, the method comprises orally (ii) hydrogen peroxide in a stable, or Substantially stable, administering an effective amount of a binding system taught non-covalent association. hereinto the Subject. The binding system can prevent, inhibit, US 2014/03701 18 A1 Dec. 18, 2014

or ameliorate the symptoms of irritable bowel syndrome in pharmaceutical carriers include, but are not limited to, sterile the Subject when compared to a second subject in a control liquids, Such as water, oils and lipids such as, for example, group in which the binding system was not administered. In phospholipids and glycolipids. These sterile liquids include, Some embodiments, the symptom is selected from the group but are not limited to, those derived from petroleum, animal, consisting of a stool score, heartburn, indigestion, urgency of Vegetable or synthetic origin such as, for example, peanut oil, defecation, nausea, vomiting, stomach pain, and bloating. soybean oil, mineral oil, sesame oil, and the like. Suitable 0090. As described herein, the binding systems can be pharmaceutical excipients include, but are not limited to, used in a method of treating an inflammatory bowel disease in Starch, Sugars, inert polymers, glucose, lactose, Sucrose, gela a Subject. In some embodiments, the method comprises orally administering an effective amount of a binding system taught tin, malt, rice, flour, chalk, silica gel, sodium Stearate, glyc hereinto the Subject. The binding system can prevent, inhibit, erol monostearate, talc, sodium chloride, dried skim milk, orameliorate the symptoms of inflammatory bowel disease in glycerol, propylene, glycol, water, ethanol, and the like. The the Subject when compared to a second subject in a control composition can also contain minor amounts of wetting group in which the binding system was not administered. In agents, emulsifying agents, pH buffering agents, or a combi Some embodiments, the symptom is selected from the group nation thereof. The compositions can take the form of solu consisting of a stool score, heartburn, indigestion, urgency of tions, Suspensions, emulsion, tablets, pills, capsules, pow defecation, nausea, vomiting, stomach pain, and bloating. ders, sustained-release formulations and the like. Oral formulations can include standard carriers such as, for 0091. As described herein, the binding systems can be example, pharmaceutical grades mannitol, lactose, starch, used in a method of treating food poisoning in a subject. In magnesium Stearate, sodium saccharine, cellulose, magne Some embodiments, the method comprises orally administer sium carbonate, and the like. See Martin, E.W. Remington's ing an effective amount of a binding system taught herein to Pharmaceutical Sciences. Supplementary active compounds the Subject. The binding system can prevent, inhibit, orame can also be incorporated into the compositions. In some liorate the symptoms of food poisoning in the Subject when embodiments, the carrier can be a solvent or dispersion compared to a second Subject in a control group in which the medium including, but not limited to, water, ethanol; a polyol binding system was not administered. In some embodiments, Such as for example, glycerol, propylene glycol, liquid poly the symptom is selected from the group consisting of a stool ethylene glycol, and the like; and, combinations thereof. The score, heartburn, indigestion, urgency of defecation, nausea, proper fluidity can be maintained in a variety of ways such as, Vomiting, stomach pain, and bloating. for example, using a coating Such as lecithin, maintaining a Methods of Administering the Compositions required particle size in dispersions, and using surfactants. 0092. The terms “administration' or “administering can 0094. The compositions can be administered to a subject be used to refer to a method of incorporating a composition orally or rectally, for example, in the treatment of a gas into the cells or tissues of a subject, either in vivo or ex vivo to trointestinal spasm.Oral administration can include digestive test the activity of a system, as well as to diagnose, prevent, tract, buccal, Sublingual, and Sublabial, and a carrier Such as a treat, or ameliorate a symptom of a disease. In one example, Solid or liquid can be used. A Solid can include, for example, a compound can be administered to a Subject in Vivo using any a pill, capsule, tablet, or time-release technology in some means of administration taught herein. In another example, a embodiments; and, for buccal or Sublingual, a solid can compound can be administered ex vivo by combining the include an orally disintegrating tablet, a film, a lollipop, a compound with cell tissue from the subject for purposes that lozenge, or chewing gum; and, a liquid can include a mouth include, but are not limited to, assays for determining utility wash, a toothpaste, an ointment, or an oral spray. A liquid can and efficacy of a composition. And, of course, the systems can include, for example, a solution, Soft gel, Suspension, emul be used in vitro to test their stability, activity, toxicity, effi Sion, syrup, elixir, tincture, or a hydrogel. cacy, and the like. When the compound is incorporated in the 0.095 Tablets, pills, capsules, troches liquids and the like Subject in combination with one or active agents, the terms may also contain binders, excipients, disintegrating agent, “administration' or “administering can include sequential or lubricants, glidants, chelating agents, buffers, tonicity modi concurrent incorporation of the compound with the other fiers, Surfactants, Sweetening agents, and flavoring agents. agents such as, for example, any agent described above. A Some examples of binders include microcrystalline cellulose, pharmaceutical composition of the invention can be formu gum tragacanth or gelatin. Some examples of excipients lated, in some embodiments, to be compatible with its include starch or maltodextrin. Some examples of disintegrat intended route of administration. ing agents include alginic acid, corn starch and the like. Some 0093. Any administration vehicle known to one of skill to examples of lubricants include magnesium Stearate or potas be suitable for administration of the compounds, composi sium Stearate. An example of a chelating agent is EDTA. tions, and formulations taught herein can be used. A“vehicle' Some examples of buffers are acetates, citrates orphosphates. can refer to, for example, a diluent, excipient or carrier with Some examples oftonicity modifiers include sodium chloride which a compound is administered to a subject. A pharma and dextrose. Some examples of surfactants for micellation or ceutically acceptable carrier is a diluent, adjuvant, excipient, increasing cell permeation include coconut Soap, anionic, or vehicle with which the composition is administered. A cationic or ethoxylate detergents. An example of a glidant is carrier is pharmaceutically acceptable after approval by a colloidal silicon dioxide. Some examples of Sweetening state or federal regulatory agency or listing in the U.S. Phar agents include Sucrose, saccharin and the like. Some macopeial Convention or other generally recognized sources examples of flavoring agents include peppermint, chamo for use in Subjects. The pharmaceutical carriers include any mile, orange flavoring and the like. It should be appreciated and all physiologically compatible solvents, dispersion that the materials used in preparing these various composi media, coatings, antibacterial and antifungal agents, isotonic tions should be pharmaceutically pure and non-toxic in the and absorption delaying agents, and the like. Examples of amounts used US 2014/03701 18 A1 Dec. 18, 2014

0096 Rectal administrations can be made using any lactic, such that the condition has not actually onset or pro method known to one of skill. For example, a Suppository duced symptoms. Dosage regimens may be adjusted over formulation can be prepared by heating glycerin to about time according to the individual need and the professional 120° C., combining the binding system with the heated glyc judgment of the person administering or Supervising the erin, mixing the combination, adding purified water to a administration of the compositions, and the dosage ranges set desired consistency, and pouring the desired consistency into forth herein are exemplary only and do not limit the dosage a mold to form the Suppository. ranges that may be selected by medical practitioners. The 0097. The compositions may be administered as suspen compounds can be administered in dosage units. The term sions or emulsions. Lipophilic Solvents or vehicles include, “dosage unit can refer to discrete, predetermined quantities but are not limited to, fatty oils such as, for example, Sesame of a compound that can be administered as unitary dosages to oil; synthetic fatty acid esters, such as ethyl oleate or triglyc a Subject. A predetermined quantity of active compound can erides; and liposomes. Suspensions that can be used for injec be selected to produce a desired therapeutic effect and can be tion may also contain Substances that increase the viscosity of administered with a pharmaceutically acceptable carrier. The the Suspension Such as, for example, sodium carboxymethyl predetermined quantity in each unit dosage can depend on cellulose, Sorbitol, or dextran. Optionally, a suspension may factors that include, but are not limited to, (a) the unique contain stabilizers or agents that increase the solubility of the characteristics of the active compound and the particular compounds and allow for preparation of highly concentrated therapeutic effect to be achieved, and (b) the limitations Solutions. In some embodiments, an administration, such as inherent in the art of creating and administering Such dosage an oral or rectal administration, for example, may include units. liposomes. In some embodiments, the liposome may assist in 0101. An "effective amount of a compound can be used a targeted delivery system. The liposomes can be designed, to describe a therapeutically effective amount or a prophylac for example, to bind to a target protein and be taken up tically effective amount. An effective amount can also be an selectively by the cell expressing the target protein. amount that ameliorates the symptoms of a disease. A “thera 0098. In some embodiments, isotonic agents can be used peutically effective amount can refer to an amount that is Such as, for example, Sugars; polyalcohols that include, but effective at the dosages and periods of time necessary to are not limited to, mannitol, Sorbitol, glycerol, and combina achieve a desired therapeutic result and may also refer to an tions thereof; and sodium chloride. Sustained absorption amount of active compound, prodrug orpharmaceutical agent characteristics can be introduced into the compositions by that elicits any biological or medicinal response in a tissue, including agents that delay absorption Such as, for example, system, or subject that is sought by a researcher, veterinarian, monostearate salts, gelatin, and slow release polymers. Car medical doctor or other clinician that may be part of a treat riers can be used to protect against rapid release, and Such ment plan leading to a desired effect. In some embodiments, carriers include, but are not limited to, controlled release the therapeutically effective amount should be administered formulations in implants and microencapsulated delivery in an amount Sufficient to result in amelioration of one or systems. Biodegradable and biocompatible polymers can be more symptoms of a disorder, prevention of the advancement used Such as, for example, ethylene vinyl acetate, polyanhy of a disorder, or regression of a disorder. In some embodi drides, polyglycolic acid, collagen, polyorthoesters, polylac ments, for example, a therapeutically effective amount can tic acid, polycaprolactone, polyglycolic copolymer, and the refer to the amount of an agent that provides a measurable like. Such formulations can generally be prepared using response of at least 5%, at least 10%, at least 15%, at least methods known to one of skill in the art. 20%, at least 25%, at least 30%, at least 35%, at least 40%, at 0099. In some embodiments, the composition is adminis least 45%, at least 50%, at least 55%, at least 60%, at least tered in a Sustained release formulation, and the formulation 65%, at least 70%, at least 75%, at least 80%, at least 85%, at can include one or more agents in addition to the composition. least 90%, at least 95%, or at least 100% of a desired action of In Some embodiments, the Sustained release formulations can the composition. reduce the dosage and/or frequency of the administrations of 0102. In some embodiments, the desired action of the Such agents to a subject. In some embodiments, an exogenous composition is relief of a gastrointestinal spasm. The relief catalyst or enzyme is introduced to a target and one or more of can include, for example, reducing or eliminating abdominal the reactive oxygen species, phenolic compound, or the exo pain, bloating, forceful defecation, forceful vomiting, defeca geneous catalyst or enzyme are segregated by encapsulation tion urgency, constipation, and/or incontinence. In these or micellation to delay the bioactivation until target site is embodiments, at least 10% relief can be obtained in a time reached by all components. ranging from 1 minute to 24 hours, from about 5 minutes to 0100. One of skill understands that the amount of the about 18 hours, from about 10 minutes to about 12 hours, agents administered can vary according to factors such as, for from about 20 minutes to about 8 hours, from about 30 min example, the type of disease, age, sex, and weight of the utes to about 6 hours, from about 1 hours to about 4 hours, Subject, as well as the method of administration. For example, from about 2 hours to about 10 hours, from about 3 hours to an administration can call for Substantially different amounts about 9 hours, or any range or amount therein in increments of to be effective. Dosage regimens may also be adjusted to 5 minutes. optimize a therapeutic response. In some embodiments, a 0103) A "prophylactically effective amount can refer to single bolus may be administered; several divided doses may an amount that is effective at the dosages and periods of time be administered over time; the dose may be proportionally necessary to achieve a desired prophylactic result, such as reduced or increased; or, any combination thereof, as indi prevent the onset of an inflammation, allergy, nausea, diar cated by the exigencies of the therapeutic situation and factors rhea, infection, and the like. Typically, a prophylactic dose is known one of skill in the art. It is to be noted that dosage used in a Subject prior to the onset of a disease, or at an early values may vary with the severity of the condition to be stage of the onset of a disease, to preventor inhibit onset of the alleviated, as well as whether the administration is prophy disease or symptoms of the disease. A prophylactically effec US 2014/03701 18 A1 Dec. 18, 2014 tive amount may be less than, greater than, or equal to a a faster response to the treatment, a more selective response to therapeutically effective amount. the treatment, or a combination thereof. In some embodi 0104. In some embodiments, a therapeutically or prophy ments, the methods taught herein can further include the lactically effective amount of a composition may range in administration of an antibiotic, an anti-emetic, an anticholin concentration from about 0.01 nM to about 0.10 M. from ergic, an antispasmodic, or an anticancer agent. about 0.01 nM to about 0.5M; from about 0.1 nM to about 0107 Antibiotics can include, for example, aminoglyco 150 nM; from about 0.1 nM to about 500 uM; from about 0.1 sides, ansamycins, carbacephem, carbapenems, cephalospor nM to about 1000 nM, 0.001 uM to about 0.10 M: from about ins (first through fifth generation), glycopeptides, lincosa 0.001 uM to about 0.5M; from about 0.01 uM to about 150 mides, macrollides, monobactams, penicillins, penicillin uM; from about 0.01 uM to about 500 uM; from about 0.01 combinations, polypeptides, quinolones, Sulfonamides, tetra uM to about 1000 nM, or any range therein. In some embodi cyclines, and drugs against mycobacteria. In some embodi ments, the compositions may be administered in an amount ments, the antibiotic is selected from the group consisting of ranging from about 0.005 mg/kg to about 100 mg/kg, from natural penicillin, cephalosporin, amoxicillin, ampicillin, about 0.005 mg/kg to about 400 mg/kg; from about 0.01 clavamox, polymyxin, tetracycline, chlortetracycline, doxy mg/kg to about 300 mg/kg, from about 0.01 mg/kg to about cycline, chloramphenicol, erythromycin, oleandomycin, 250 mg/kg, from about 0.1 mg/kg to about 200 mg/kg, from streptomycin, gentamicin, kanamycin, tombramycin, nalid about 0.2 mg/kg to about 150 mg/kg, from about 0.4 mg/kg to ixic acid, rifamycin, rifampicin, prontisil, gantrisin, trimetho about 120 mg/kg, from about 0.15 mg/kg to about 100 mg/kg, prim, isoniazid, para-aminosalicylic acid, and ethambutol. from about 0.15 mg/kg to about 50 mg/kg, from about 0.5 One of skill will appreciate that subgroups of this group can mg/kg to about 10 mg/kg, or any range therein, wherein a be desired in Some embodiments. Anti-emetics can include, human Subject is often assumed to average about 70 kg. for example, anticholinergic agents, antidopaminergic 0105. The amount of the composition administered may agents, 5-HT3 antagonists, H1 antihistamines, cannabinoids, vary widely depending on the type of formulation, size of a corticosteroids, and benzodiazepines. In some embodiments, unit dosage, kind of excipients, and other factors well known the anti-emetics can be selected from the group consisting of to those of ordinary skill in the art. A formulation may com benzodiazepines such as diazepam or lorazepam, 5-HT prise, for example, an amount of the composition ranging receptor antagonists such as ondansetron, tropisetron, gran from about 0.0001% to about 6% (w/w), from about 0.01% to isetron, and dolasetron. Antispasmodics can include, for about 1%, from about 0.1% to about 0.8%, or any range example, anticholinergics such as dicyclomine and hyos therein, with the remainder comprising the excipient or cyamine, as well as mebeverine and papaverine, for example. excipients. In some embodiments, the compositions can be Anticancer agents can include, for example, alkylating administered, for example, in an amount of ranging from agents, antimetabolites, anthracyclines, plant alkaloids, about 0.1 g/kg to about 1 mg/kg, from about 0.5 ug/kg to topoisomerase inhibitors, and other antitumor agents. One of about 500 ug/kg, from about 1 ug/kg to about 250 g/kg, from skill will appreciate that the agents listed above can be used about 1 g/kg to about 100 ug/kg from about 1 ug/kg to about alone, or in combination, in some embodiments. For example, 50 ug/kg, or any range therein. One of skill can readily select chemotherapy and anti-emetics can be administered together. the frequency and duration of each administration. For And, anti-emetics can be administered together, such as a example, depending on the gastrointestinal disorder treated, combination of corticosteroids and a second anti-emetic Such whether a prophylactic treatment or a treatment of an existing as an antihistamine, anticholinergic, benzodiazepine, can disorder, variables Such as the age and size of the Subject can nabinoid, or an anti-dopaminergic agent. be considered, as well as the source and type of the polyphe 0.108 Combinations therapies can be administered, for nol component and the intensity of the symptoms. In these example, for 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 embodiments, the compositions can be administered orally in hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, daily doses ranging from about 5 ug to about 5000 ug dry 7 days, 8 days, 9 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 6 weight, for example. In such embodiments, the compositions weeks, 3 months, 6 months 1 year, any combination thereof, can be administered orally in amounts ranging from about 5 or any amount of time considered necessary by one of skill. ug to about 5000 ug, from about 10 ug to about 4000 ug, from The agents can be administered concomitantly, sequentially, about 20 ug to about 3000 ug, from about 50 ug to about 2000 orcyclically to a subject. Cycling therapy involves the admin ug, from about 100 ug to about 1000 ug, from about 250 ug to istering a first agent for a predetermined period of time, about 500 ug, or any range therein, in dry weight. In some administering a second agent or therapy for a second prede embodiments, the compositions can be administered orally in termined period of time, and repeating this cycling for any daily doses of about 100 g, about 200g, about 300 g, about desired purpose Such as, for example, to enhance the efficacy 400 ug, about 500 ug, about 600 ug, about 700 ug, about 800 of the treatment. The agents can also be administered concur ug, about 900 g, about 1000 ug, about 2000 ug, about 3000 rently. The term “concurrently' is not limited to the admin ug, about 4000 ug, about 5000 g, about 6000 ug, about 7000 istration of agents at exactly the same time, but rather means ug, about 8000 ug, about 9000 ug, or any range therein in that the agents can be administered in a sequence and time increments of 50 ug dry weight. interval Such that the agents can work together to provide 0106. In some embodiments, the composition can be additional benefit. Each agent can be administered separately administered in conjunction with at least one other therapeu or together in any appropriate form using any appropriate tic agent for the condition being treated. The amounts of the means of administering the agent or agents. agents can be reduced, even Substantially, Such that the 0109 The compositions taught herein can be used in co amount of the agent or agents desired is reduced to the extent administrations with nutritional therapy or rehydration thera that a significant response is observed from the Subject. A pies. In some embodiments, the composition can be co-ad significant response can include, but is not limited to, a reduc ministered with at least one other nutritional and/or tion or elimination of nausea, a visible increase in tolerance, rehydrating agent for aiding recovery from a health imbal US 2014/03701 18 A1 Dec. 18, 2014

ance, or to maintain a health balance. Examples of rehydrat flator, intravenous (I.V.) bag, envelope, and the like; and at ing agents can include, but are not limited to, GATORADE least one unit dosage form of an agent comprising an extract and other electrolyte drinks, oral rehydration solutions taught herein within the packaging material. There can be a (ORSs) generally, new oral rehydration solution (N-ORS), first composition comprising at least one unit dosage form of SEURO ORAL PEDIAONE, and PEDIALYTE. Examples an agent comprising a binding system as taught herein within of nutritional Supplements can include, but are not limited to, the packaging material, and optionally, a second composition Zinc sulfate, Salted rice water, Salted yogurt-based drinks, and comprising a second agent Such as, for example, any other vegetable or chicken soup with salt. Such health imbalances bioactive agent that may be administered in combination with can include, but is not limited to, dehydration, malnutrition, the binding system, or any prodrugs, codrugs, metabolites, electrolyte imbalance, vitamin deficiency, food hypersensi analogs, homologues, congeners, derivatives, salts, Solvates, tivities, stress induced diarrhea, abdominal cramping, and and combinations thereof. In some embodiments, the articles alcohol hangover, or a combination thereof. In some embodi of manufacture may also include instructions for using the ments, the methods taught herein can further include the composition as a diagnostic, prophylactic, therapeutic, or administration of oral rehydrating or nutritional agents such ameliorative treatment for the condition of concern. In some as sodium, potassium, dextrose, fructose, glucose, magne embodiments, the instructions can include informational sium, Zinc, Selenium, Vitamin A, Vitamin D. Vitamin C, material indicating how to administer the systems for a par dietary fiber, and combinations thereof. The amounts and ticular use or range of uses, as well as how to monitor the ratios of the agents to the composition can be substantially Subject for positive and/or negative responses to the systems. varied to provide prophylaxis, therapy or maintenance of 0113. In some embodiments, the article of manufacture healthful balance. Ratios of the compositions herein to the can include a Substantially anhydrous binding system. For nutritional agents or rehydration agents can range, for example, a kit can be assembled which includes the anhy example, from about 1:100 to about 100:1, from about 1:50 to drous binding system comprising an anhydrous tannin with about 50:1, from about 1:40 to about 40:1, from about 1:30 to instructions combining the tannin with and an anhydrous about 30:1, from about 1:20 to about 20:1, from about 1:10 to reactive species generating component that forms a therapeu about 10:1, from about 1:5 to about 5:1, from about 1:4 to tically, prophylactically, or nutritionally useful composition about 4:1, from about 1:3 to about 3:1, from about 1:2 to about upon hydration. 2:1, from about 1:1.5 to about 1.5:1, about 1:1, or any range 0114 Kits for the treatment of gastrointestinal spasms are therein. The ratios can be based on Volume: Volume, mass: provided herein. In these embodiments, the kits can include Volume, Volume:mass, mass: mass, or molar:molar. It should the polyphenol component and/or the reactive oxygen species be appreciated that the concentrations of the compositions in a wet or dry form. Optionally, the kits can include instruc taught herein can be the same or different than the concentra tions for use in treating a subject. The instructions can tions of the nutritional agents or rehydration agents. And, it include, for example, instructions on diluting the composition should also be appreciated that the concentrations and ratios to a desired concentration and administration according to of concentrations can be subjective to a particular adminis Suggested dilution factors on the basis of ages and weights of tration, such that they can be independently selected accord Subjects, as well as known conditions and target sites. The ing to the condition treated, objective sought, desired effect, Suggested dilution factors can be selected from the ranges and/or personal preference. The combinations can be admin taught herein. In some embodiments, the kits comprise a dry, istered under any regime taught herein for the administration stable form of the composition components. For example, the of an agent or combination of agents. kits can comprise a dry form of a polyphenol component, Such as one polyphenol, a combination of polyphenols, or an Articles of Manufacture extract of a plant tissue having polyphenols. Moreover, the 0110 Articles of manufacture that encompass finished, kits can also comprise a dry form of a hydrogen peroxide packaged and labelled products are provided. The articles of generating material that functions to generate an effective manufacture include the appropriate unit dosage form in an amount of an exogeneous reactive oxygen species, wherein appropriate vessel or container Such as, for example, a glass the reactive oxygen species includes a component selected vial or other container that is hermetically sealed. In the case from the group consisting of hydrogen peroxide, Superoxide of dosage forms suitable for oral administration, the active anion, singlet oxygen, and a hydroxyl radical. In these ingredient, e.g. one or more agents including a dosage form embodiments, the composition can be at least Substantially taught herein, may be suitable for administration orally, rec free of active endogeneous oxidative enzymes and catalytic tally, or the like. Substances that cause degradation of the composition. 0111 AS with any such product, the packaging material Example 1 and container are designed to protect the stability of the product during storage and shipment. In addition, the articles Making and Testing an Antispasmodic Composition of manufacture can include instructions for use or other infor mation material that can advise the user Such as, for example, 0115 This experiment includes the use of gallic acid, tan a physician, technician or patient, regarding how to properly nic acid, a pomegranate husk extract, and a green tea extract. administer the composition as a prophylactic, therapeutic, or 0116. Measuring the Amount of Hydrogen Peroxide that ameliorative treatment of the disease of concern. In some Remains Bound to the Polyphenol embodiments, instructions can indicate or suggest a dosing 0117. One of skill knows that hydrogen peroxide does not regimen that includes, but is not limited to, actual doses and exist in a pure, Solid form under normal conditions, for monitoring procedures. example, ambient conditions. However, this example shows 0112. In some embodiments, the articles of manufacture that the hydrogen peroxide can exist in dry form when in can comprise one or more packaging materials such as, for association with the model compounds and plant extracts, and example, a box, bottle, tube, Vial, container, sprayer, insuf the compositions have been isolated in a dry form as proof. US 2014/03701 18 A1 Dec. 18, 2014

Art-recognized procedures, such as those set-forth at least in compositions contain a Substantial amount of a stabilized U.S. Pat. Nos. 3,860,694; 3,864,454; 4,171,280; and 4,966, hydrogen peroxide that is carried with the model compounds 762, were used as a guide for this study. or extracts as a dry form. 0118. The model compounds were used to show that the 0.125. The stability of the hydrogen peroxide in the com compounds include hydrogen peroxide, the reactive oxygen bination is greater in an aqueous solution than the stability of species component, in a relatively stable association with the the hydrogen peroxide alone in the aqueous Solution polyphenol component. As discussed, one of skill will appre 0.126 This method tests the stability of the hydrogen per ciate that hydrogen peroxide in a free form, for example, oxide in the combination. The testing methods used follow would otherwise quickly degrade. The polyphenols were pro the standard procedures set-forth by the Clinical and Labo vided from model compounds or plant extracts. A dry form of ratory Standards Institute (CLSI) and US Pharmacopeia. the compositions was made between (i) gallic acid (a model 0.127 i. E. coli was chosen as the bacteria to challenge polyphenol building block from Sigma-Aldrich) and hydro the stability of the bound compositions and the free gen peroxide; (ii) tannic acid (a model polyphenol component hydrogen peroxide. from Sigma-Aldrich) and hydrogen peroxide; (iii) pomegran 0.128 ii. The hydrogen peroxide concentration was ate husk extract and hydrogen peroxide; and, (iv) green tea matched to the selected bacteria in order to form a useful extract and hydrogen peroxide, using the procedures taught curve representing hydrogen peroxide degradation over herein, including: time for the samples. As such, the hydrogen peroxide was varied from 62.5 ppm to 500 ppm on a fixed E. coli 0119 i. adding a solution of 35% hydrogen peroxide concentration of 10 CFU/ml, and a concentration of slowly into each of the gallic acid powder, tannic pow 125 ppm was chosen as the initial hydrogen peroxide der, pomegranate husk extract powder, or green tea level used to challenge the E. coli over time. extract powder. The adding is done in a glass dish or 0.129 iii. A ratio of 1:1 of the hydrogen peroxide to each beaker at 45-65 C. under constant, gentle mixing; of the model compounds and plant extracts was used to I0120 ii. creating a dry form of the composition by form each bound composition, Such that 125 ppm of continuing the heating under the constant, gentle mixing each plant extract was combined with the 125 ppm of the until fine dry granules or hard amorphous chunks form; hydrogen peroxide. 0121 iii. crushing the granules or chunks into a powder, 0.130 iv. The free hydrogen peroxide was added at a which is the dry form; dissolving the powder into water, concentration of 125 ppm as a control to show the rela knowing that the dry forms will not have stable, free tive stability of the hydrogen peroxide alone in the aque hydrogen peroxide, such that the dissolved powder will ous solution as compared to the bound compositions. I0131 FIGS. 2A and 2B show that the stability of the carry only the stabilized hydrogen peroxide associated hydrogen peroxide in the combination is consistently, Sub with the model compounds or extracts; and, stantially greater in an aqueous Solution than the stability of 0.122 iv. measuring the total hydrogen peroxide con the hydrogen peroxide alone in the aqueous solution, accord centration associated with the model compounds or ing to some embodiments. FIG. 2A compares stabilities of extracts in the dry form. free hydrogen peroxide to hydrogen peroxide bound to each 0123. The hydrogen peroxide concentration measure of gallic acid (a model polyphenol building block), tannic ments were taken using standard methods to determine the acid (a model polyphenol), pomegranate husk extract, green amount of hydrogen peroxide that bound to the model com tea extract, and Blessed thistle extract. FIG. 2B shows very pounds or extracts in the dry form. It was found that (i) about similar and consistent stabilities when comparing free hydro 3.0% hydrogen peroxide bound to the gallic acid (a model gen peroxide to hydrogen peroxide bound to a wide variety of polyphenol building block) by total dry wt; (ii) about 2.5% species of plants: Aloe, Angelica, Barberry Root Bark, Bil hydrogen peroxide bound to the tannic acid (a model berry, Calendula, Cramp bark, Eleutherococcus root, Kidney polyphenol component) by total dry wt; (iii) about 1.8% wood, Mimosa tenuiflora, Papaya leaves, Paul D'Arco, Sas hydrogen peroxide bound to the pomegranate husk extract by safras albidum root bark, Saw Palmatto, St. John’s wort, total dry wit; and, (iv) about 2.0% hydrogen peroxidebound to Valerian, Apple, Grape, Echinacea purpurea, Grape seed the green tea extract by total dry wt. To measure the hydrogen extract, and Blueberry. In both FIGS. 2A and 2B, there are peroxide levels, a standard, WATERWORKS peroxide test curves that cannot be identified well individually, as they are strip method was used having a test sensitivity of 0.5, 2, 5, 10. identical and overlapping. The free hydrogen peroxide curve 25, 50, 100 ppm, available from Industrial Test Systems, Inc., does not overlap with any of the bound compositions beyond Rock Hill, S.C. 29730. the 4 hour mark. Table 1 provides data used to produce the curves in the overlap for clarity. 0.124 FIGS. 1A-1H are photographs of the dry forms of (A) gallic acid (a model polyphenol building block) bound to hydrogen peroxide; (B) gallic acid alone; (C) tannic acid (a TABLE 1 model polyphenol) bound to hydrogen peroxide: (D) tannic Hours acid alone; (E) pomegranate husk extract bound to hydrogen peroxide; (F) pomegranate husk extract alone; (G) green tea extract bound to hydrogen peroxide; and (H) green tea extract Aloe (Aloe Vera) 125 30 25 20 15 15 10 alone, according to some embodiments. As can be seen, the Angelica (Angelica archangelica) 125 16 1S 12 1 0 1 0 12 Barberry (Berberis vulgaris) Root 12S 30 20 15 10 1 0 12 dry compositions exist and do contain a stable amount of Bark hydrogen peroxide in an amount ranging from about 1.8% to Bilberry (Vaccinium myrtillus) 125 30 25 20 15 12 15 about 3.0%, indicating the stabilizing association between the Calendula (Calendula officinalis) 125 16 1S 12 1 0 1 0 10 combined model compounds and extracts with the hydrogen Cramp bark (Viburnum opulus) 125 16 12 1 0 1 0 12 12 peroxide. One of skill will appreciate that, Surprisingly, the US 2014/03701 18 A1 Dec. 18, 2014

TABLE 1-continued centration of 0.004.5% hydrogen peroxide and 100 micro grams of polyphenols before administration. Unused and Hours undiliuted solutions of the composition from the same lot were tested for hydrogen peroxide concentration using stan O 4 8 12 16 20 24 dard methodologies, described herein, verifying an Eleutherococcus root 25 6 12 1 0 1 0 1 0 10 unchanged ratio of peroxide to polyphenols. The free hydro (Eleutherococci is senticosus) Kidney wood (Eysenhardtia 25 6 12 1 0 1 0 1 0 10 gen peroxide at the fully diluted oral concentration was well orththocarpa) below its conventionally accepted minimum inhibitory con Mimosa tenuiflora 25 30 25 15 10 12 15 centration for most bacteria. Papaya (Carica papaya) leaves 25 6 12 1 0 1 0 12 15 Pau D'Arco (Tabebuia avellanedae) 2S 20 15 10 1 0 12 10 0.136 The composition was tested for stability. Consistent Sassafras albidum root bark 2S 20 15 10 1 0 1 0 12 with the methods taught herein, the composition was dessi Saw Palmatto (Serenoa repens) 25 S 12 1 0 1 0 1 0 12 cated to a gummy Solid with slow heating in a glass dish or St John's wort (Hypericum 2S 40 25 20 12 15 12 perforatin) beaker at 45-65°C. under constant, gentle mixing, along with Valerian (Valeriana officinalis) 2S 20 15 12 1 0 1 0 12 vacuum dessication to degrade free hydrogen peroxide. The Apple (Maius domestica) 25 S 11 1 0 1 0 1 0 10 composition was then rehydrated to its original liquid Volume Grape (Vitis vinifera) 2S 30 20 15 15 12 12 to determine the amount of hydrogen peroxide that was stable Echinacea purpurea 25 6 1S 12 12 1 0 10 enough to remain in the composition. And, to compare the Grape seed extract 2S 30 20 15 10 1 0 10 Blueberry (Vaccinium corymbosum) 2S 20 15 12 1 0 1 0 10 composition to those prepared from other plant tissues, the H2O2 2S 15 O O O O O same test was performed with a variety of polyphenol extracts including grape skin extract, guava leaf extract, green tea extract only, pomegranate rind only, Aloe vera skin extract, 0132) The results were quite impressive and surprising, as and knotweed extract. All of the compositions retained a the free hydrogen peroxide degraded quickly to near 0.0 ppm Substantial concentration of a stable, hydrogen peroxide each time within about the first 8 hours, whereas each of the through the dessication and rehydration cycle, providing evi bound compositions maintained at least 10 ppm or greater for dence that water extracts from different plant sources provide the total duration of the study, which was limited due to time a source of polyphenols that form similar stable compositions constraints. As such, it was observed that the stabilities were with hydrogen peroxide. maintained at a concentration of at least 10 ppm or greater for at least 24 hours, a concentration Sufficient to maintain bac 0.137 The Study tericidal activity in water. FIG. 2A shows that at least 7 days 0138 Significant responses to administration of the com of stability remained present in at least the samples that were position were observed. Of the 29 patients, 4 complained of afforded the at least 7 days of testing. In fact, potencies have constipation and 2 showed improvement. The 6 out of the 13 been observed to remain in the compositions when chal with gluten sensitivity (a test used in the diagnosis of IBS) lenged for at least 30 days, and the original batches have reported reduced incidence of bloating, abdominal pain, shown to remain potent for at least 90 days, in Some cases. bowel urgency or soft/water stools following gluten intake, Suggesting that the composition is an effective treatment for Example 2 irritable bowel syndrome. 19 out of the 29 (65%) subjects generally reported an improved health and relief of symp Treating Gastrointestinal Spasms in Patients Having toms. 11 out of 16 (69%) of the subjects, a rather high per Irritable Bowel Syndrome centage, reported improvement in gastrointestinal spasm symptoms. It has been observed, generally, that Subjects 0133) A physician-controlled, open-label pilot study of 29 receiving the composition have reported significant improve patients was performed. The patients Suffered chronic gas trointestinal symptoms, including gastrointestinal spasms, ments over their historic baseline health within 24 hours. and were selected because they were either non-responsive, 0.139 A Literature Comparison or merely partially responsive, to standard treatments. The 0140. As described above, loperamide can be used to treat patients had been diagnosed with irritable bowel syndrome symptoms of IBS. As an agent for IBS patients, loperamide (IBS) and ranged in age from 29 years old to 79 years old, has been reported to resolve abdominal pain symptoms in having a mean age of 51 years old. 83% of the patients were 56% to 59% of patients in one study but to be no different female. The patients were provided with sufficient volume of from placebo in other studies. See, for example, Kaplan MA, the composition for five days of consumption and asked to et al. Arch Fam Med 8: 243-248 (1999); Efskind, PS, et al. note any response or effects of the extract. Each of the patients Scand J. Gastroenterol 31: 463-468 (1996); Cann PA, et al. received a 25ml bottle of the test composition and instructed Dig Dis Sci 29(3): 239-247 (1984); and, Jailwala J, T F to take 5 ml per day with water at least 1 hour before meals for Imperiale, K Kroenke. Ann Intern Med 133: 136-147 (2000). a 5 day period. The patients had been under treatment for Antispasmotic medications have been reported to result in a chronic GI distress for an extended period and were asked to higher level of relief of abdominal pain than placebo, with up compare the performance of the test composition against their to 56% of patients experiencing a result that was clinically own subjective baseline health. meaningful. See, for example, Trinkley KE, et al. J. Clin 0134. The Test Composition Pharm Thera 36: 275-282 (2011); and, Page JG, et al. J. Clin 0135. The test solution (“the composition” or “the test Gastroenterol 3: 153-156 (1981). composition') contained approximately 1100 micrograms 0.141. In comparison, the results to date Suggest that the total dry weight of dessicated pomegranate and green tea compositions taught herein offer a significant improvement extract dissolved in a solution of 0.05% hydrogen peroxide in over the results that have been observed in the literature for purified water. 25 ml was of the solution was then further loperamide, for example, at least with regard to the treatment diluted in 250 ml of oral rehydration solution to a final con of IBS. US 2014/03701 18 A1 Dec. 18, 2014

0142. Other Studies trointestinal spasm, the composition having a water 0143. Other compositions using polyphenols derived from soluble polyphenol that was (i) water-extracted from a water extractions from other plants have been tested and mixture of pomegranate husk and green tea leaf and (ii) shown to provide similar results. In one study, grape skin combined with hydrogen peroxide prior to the adminis extract and guava leaf extract have been combined with com tering: mercial food grade hydrogen peroxide and plant extracted wherein, hydrogen peroxide from aloe veragel. This composition was the hydrogen peroxide concentration ranges from about administered to human Subjects Suffering from abdominal 0.001% to about 2.0% based on total dry weight of the cramps. In all cases, the administration provided effective composition; relief, evidence that other sources of water soluble polyphe the polyphenol comprises a tannin; nol extracts provide commercially valuable and effective antispasmodic compositions. the polyphenol has a molecular weight ranging from about 0144. In another study, 46 adults (including 6 having IBS) 170 Daltons to about 4000 Daltons; and, experiencing Vomiting, abdominal pain, cramps, and bloating the composition relieves the malnutrition in the subject by were given the 25ml solution of the combination of compo relieving the associated gastrointestinal spasm when sition (green tea/pomegranate/HO) and reported near-im compared to a second Subject in a control group also mediate relief with a significant reduction in Symptoms having malnutrition with an associated gastrointestinal remaining after 24 hours of treatment when compared to a spasm in which the composition was not administered. placebo group. 78% reported significant benefit. 2. The method of claim 1, further comprising adding a nutritional Supplement selected from the group consisting of Example 3 Sodium, potassium, dextrose, fructose, glucose, magnesium, zinc, selenium, Vitamin A, Vitamin D. Vitamin C, dietary Prophylactic Inhibition or Prevention of Alcohol fiber, and combinations thereof. Overindulgence 3. The method of claim 1, wherein the hydrogen peroxide concentration ranges from about 0.001% to about 1.5% based 0145 Experimental prophylactic use of the compositions on total dry weight of the composition. has shown in a variety of subjects that it can inhibit or prevent gastrointestinal symptoms of the over consumption of alco 4. The method of claim 1, wherein the hydrogen peroxide hol. Surprisingly, it was also effective at inhibiting or prevent concentration ranges from about 0.001% to about 1.0% based ing other symptoms of excess alcohol consumption. For on total dry weight of the composition. example, the symptoms that have been prevented or inhibited 5. The method of claim 1, wherein the relief of the spasm is have been measured against the historic baseline of the sub measured using a response selected from the group consisting ject, including an alcohol-induced headache; and, alcohol of a reduction in abdominal pain, a reduction in bloating, a induced dermal and other tissue reactions such as apparent reduction inforceful defecation, a reduction inforceful vom immune-type, allergenic reactions that included itchiness, iting, a reduction in defecation urgency, a reduction in con blotchiness, flushing, red eyes, and runny nose. stipation, and a reduction in incontinence. 0146 Prior to the consumption of alcohol at a social event, 6. The method of claim 1, wherein the polyphenol com each of the subjects consumed approximately 2000 ug-5000 prises a hydrolysable tannin. ug of a green tea/pomegranate composition (dry weight) with 7. The method of claim 1, wherein the polyphenol com water. The green tea/pomegranate that was administered was prises a water Soluble condensed tannin. from a variety of lots and varied in ratio from 1:1 to 4:1 wit/wt. 8. The method of claim 1, wherein the polyphenol com The Subjects consumed approximately 2-10 alcoholic drinks, prises a combination of a hydrolysable tannin and a water mixed and/or straight, ranging in content from about 5% to soluble condensed tannin. about 60% alcohol. The drinks ranged in content from wine to 9. The method of claim 1, wherein the polyphenol com beer to liqueurs to liquors, and combinations thereof. Each of prises a flavanol. the Subjects expressed that the composition provided a Sub 10. The method of claim 1, wherein the polyphenol com stantial prophylactic effect to inhibit or prevent the effects of prises a catechin. the alcohol consumption, using their own, personal historic baselines of what they expected to experience without con 11. The method of claim 1, wherein the polyphenol com Suming the composition prior to drinking. prises gallic acid, epigallic acid, or a combination thereof. 0147 The experiments shown herein are for illustration 12. The method of claim 1, wherein the composition is and example only. One of skill can vary the experimental administered in combination with an oral rehydration solu conditions and components to Suit a particular or alternate tion. experimental design. The experimental conditions can be in 13. The method of claim 1, wherein the polyphenol an vitro or in Vivo, or designed for any subject, for example, ellagitannin and a gallotannin. human or non-human. For example, animal testing can be 14. The method of claim 1, wherein the polyphenol varied to Suit a desired experimental method. As such, one of includes a punicalagin. skill will appreciate that the concepts can extend well-beyond 15. A method of treating malnutrition in a Subject, com the examples shown, a literal reading of the claims, the inven prising: tions recited by the claims, and the terms recited in the claims. administering an effective amount of a composition to a We claim: Subject having malnutrition with an associated gas 1. A method of treating malnutrition in a Subject, the trointestinal spasm, the composition produced from a method comprising: process including administering an effective amount of a composition to a extracting a water soluble polyphenol from a combination Subject having malnutrition with an associated gas of green tea leaf and pomegranate husk, US 2014/03701 18 A1 Dec. 18, 2014 19

combining the polyphenol with hydrogen peroxide prior to 22. The method of claim 15, wherein the polyphenol com the administering; wherein, the polyphenol has a prises a combination of a hydrolysable tannin and a water molecular weight ranging from about 170 Daltons to soluble condensed tannin. about 4000 Daltons; 23. The method of claim 15, wherein the polyphenol com Selecting a desired concentration for the composition; and, prises a flavanol. diluting the composition to the desired concentration for 24. The method of claim 15, wherein the polyphenol com the administering; prises a catechin. 25. The method of claim 15, wherein the polyphenol com wherein, prises gallic acid, epigallic acid, or a combination thereof. the hydrogen peroxide concentration ranges from about 26. The method of claim 15, wherein the polyphenol 0.001% to about 2.0% based on total dry weight of the includes an ellagitannin and a gallotannin. composition; 27. The method of claim 15, wherein the polyphenol the polyphenol comprises a tannin; and, includes a punicalagin. the composition relieves the malnutrition in the subject by 28. A method of treating a malnutrition in a Subject, com relieving the associated gastrointestinal spasm when prising: compared to a second Subject in a control group also administering an effective amount of a composition to a having malnutrition with an associated gastrointestinal Subject having malnutrition with an associated gas spasm in which the composition was not administered. trointestinal spasm, the composition produced from a 16. The method of claim 15, further comprising adding a process including nutritional Supplement selected from the group consisting of obtaining a water extract from a green tea leaf and a Sodium, potassium, dextrose, fructose, glucose, magnesium, water extract from a pomegranate husk, zinc, selenium, Vitamin A, Vitamin D. Vitamin C, dietary combining the water extract from the green tea leaf and fiber, and combinations thereof. the water extract from the pomegranate husk to form 17. The method of claim 15, wherein the hydrogen perox a mixture of polyphenols having a molecular weight ide concentration ranges from about 0.001% to about 1.5% ranging from about 170 Daltons to about 4000 Dal based on total dry weight of the composition. tons; and, 18. The method of claim 15, wherein the hydrogen perox adding hydrogen peroxide to the polyphenol prior to the ide concentration ranges from about 0.001% to about 1.0% administering, the hydrogen peroxide concentration based on total dry weight of the composition. selected from a group consisting of concentration 19. The method of claim 15, wherein the relief of the spasm ranges from about 0.001% to about 2.0%, from about is measured using a response selected from the group con 0.001% to about 1.5%, from about 0.001% to about sisting of a reduction in abdominal pain, a reduction in bloat 1.0%, and from about 0.001% to about 0.1%, each ing, a reduction inforceful defecation, a reduction inforceful range based on total dry weight of the composition; Vomiting, a reduction in defecation urgency, a reduction in wherein, constipation, and a reduction in incontinence. the polyphenol comprises a tannin; and, 20. The method of claim 15, wherein the polyphenol com the malnutrition in the subject by relieving the associated prises a hydrolysable tannin. gastrointestinal spasm when compared to the baseline 21. The method of claim 15, wherein the polyphenol com health of the subject prior to the administering. prises a water Soluble condensed tannin. k k k k k