# US 2021/0330640 A1 · Galloylated procyanidins for increasing intracellular nitric oxide production

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- Number: US 2021/0330640 A1
- Document ID: US20210330640A1
- Status: Published application
- Kind: A1
- Application number: 16/980,519
- Filed: 2019-03-14
- Published: 2021-10-28
- Earliest claimed: 2018-03-14
- Assignees: University of South Florida; Encore IP Management, LLC
- Inventors: Jimmy Roy HUDDLESTON; Leigh Anthony WEST; Matthew Cleary NICKERSON; Michael Louis SPERDUTI
- Web page: https://patentgrep.com/patent/US20210330640A1

## CPC

- A23L 33/105: Plant extracts, their artificial duplicates or their derivatives
- A61K 31/353: 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A23L 2/52: Adding ingredients (adding preservatives A23B70/10)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- C12G 3/055: extracted from plants
- A23L: FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF (preservation thereof A23B)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12G: WINE; PREPARATION THEREOF; ALCOHOLIC BEVERAGES (beer C12C); PREPARATION OF ALCOHOLIC BEVERAGES NOT PROVIDED FOR IN SUBCLASSES C12C OR C12H

## Abstract

A composition, workout/exercise supplement, treatment method for conditions associated with vasoconstriction, and method of extracting galloylated procyanidins. The composition includes galloylated procyanidins having a preponderance of (−)-epicatechins. The treatment methods include administering a therapeutically effective amount of galloylated procyanidins having a preponderance of (−)-epicatechins. The extraction methods include isolating galloylated procyanidins having a preponderance of (−)-epicatechins from a sample that contains polyphenols, catechins, epicatechins, and galloylated epicatechins.

## Claims

### Claim 1

A composition to treat endovascular dysfunction, the composition comprising:
one or more galloylated procyanidins having between two and five epicatechin monomers;
wherein the one or more galloylated procyanidins include epicatechin-(4-8)-epicatechin-(4-8)-epicatechin-gallate, catechin trimer gallate, catechin dimer digallate, or combinations thereof; and
a pharmaceutically acceptable excipient or carrier.

### Claim 2 (depends on 1)

The composition of claim 1, further comprising one or more additional compounds selected from the group consisting of inositol-stabilized arginine, inositol-stabilized arginine silicate, arginine silicate inositol complex (ASI), L-arginine alpha-ketoglutarate (AKG), L-citrulline, L-citrulline malate, arginine hydrochloride (HCL), sodium bicarbonate, vitamin C, ascorbic acid, sucrose, aspartate, magnesium, saccharomyces cerevisiae, valeriana officinalis root, alcohol, cannabidiol (CBD), tetrahydrocannabinol (THC), acetaminophen, dextromethorphan, doxylamine, phenylephrine, ibuprofen, naproxen, Melissa officinalis, zinc, galphimia glauca, luffa operculate, sabadilla, zincum aceticum, zincum gluconicum, dioscorea pseudojaponica, passionflower extract, 1-theanine, sceletium tortuosum, melatonin, diphenhydramine, citrus-based extracts, or agmatine sulfate.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the one or more galloylated procyanidins is obtained from raw materials selected from a group consisting of: green tea leaves, apples (peel on), apricots, pecans, pistachios, almonds and hazelnuts, cherries, peaches, blackberries, black grapes, strawberries, concord grapes, red grapes, cocoa beans, plums (black diamond raw with peel on), pears, Oolong tea, milk chocolate, fava beans, dark chocolate, cherries, cacao beans, broad beans (immature seeds), black tea, peanut skins, grape vine, blueberries and raspberries.

### Claim 4

A method of treating an endovascular dysfunction, comprising:
administering a composition to a subject, wherein the composition comprises:
a a therapeutically effective amount of one or more galloylated procyanidins having between two and five epicatechin monomers;
wherein the one or more galloylated procyanidins include epicatechin-(4-8)-epicatechin-(4-8)-epicatechin-gallate, catechin trimer gallate, catechin dimer gallate, or combinations thereof; and
a pharmaceutically acceptable excipient or carrier.

### Claim 5 (depends on 4)

The method of claim 4, wherein the therapeutically effective amount of the one or more galloylated procyanidins is equal to or greater than about 0.4 μM.

### Claim 6

(canceled)

### Claim 7 (depends on 4)

The method of claim 4, wherein a concentration of the therapeutically effective amount of the one or more galloylated procyanidins is about 5%-45% by weight.

### Claim 8 (depends on 4)

The method of claim 4, wherein the method further comprises upregulating a canonical pathway in the subject selected from the group consisting of: Actin Cytoskeleton Signaling; Cluster of Differentiation 28 (CD28) Signaling in T Helper Cells; Chemokine Signaling; cAMP response element-binding (CREB) Signaling in Neurons; chemokine receptor type 4 (CXCR4) Signaling; Ephrin Receptor Signaling; extracellular signal regulated kinase/mitogen activated protein kinase (ERK/MAPK) Signaling; Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes; N-formyl-Met-Leu-Phe (fMLP) Signaling in Neutrophils; Gonadotropin-releasing hormone (GNRH) Signaling; Glycoprotein VI (GP6) Signaling Pathway; Gα12/13 Signaling; Gαq Signaling; Gαs Signaling; IL-6 Signaling; IL-8 Signaling; Insulin Receptor Signaling; Integrin Signaling; Melatonin Signaling; Nitric Oxide Signaling in the Cardiovascular System; Noradrenaline and Adrenaline Degradation; Nuclear factor erythroid 2 (NRF2)-mediated Oxidative Stress Response; Oncostatin M Signaling; Oxidative Phosphorylation; P2Y Purigenic Receptor Signaling Pathway; p70S6K Signaling; p21 activated protein kinases (PAK) Signaling; Phospholipase C Signaling; Phosphoinositide-3-Kinases (PI3K) Signaling in B Lymphocytes; PI3K/protein kinase B (AKT) Signaling; Production of Nitric Oxide and Reactive Oxygen Species in Macrophages; Protein Kinase A Signaling; Rac Signaling; Receptor activator of nuclear factor κ B (RANK) Signaling in Osteoclasts; Regulation of Actin-based Motility by Rho; RhoA Signaling; Signaling by Rho Family guanosine triphosphate (GTP)ases; Synaptic Long Term Potentiation; Telomerase Signaling; and α-Adrenergic Signaling.

### Claim 9 (depends on 4)

The method of claim 4, wherein administration to the subject causes an increase in intracellular nitric oxide production.

### Claim 10 (depends on 4)

The method of claim 4, wherein administration to the subject causes an increase in endothelium NO synthase (eNOS).

### Claim 11 (depends on 4)

The method of claim 4, wherein administration to the subject causes an increase in inducible NO synthase (iNOS).

### Claim 12 (depends on 4)

The method of claim 4, wherein administration to the subject causes increased skeletal muscle pump, increased blood flow, increased blood oxygenation, lower blood pressure, increased cognizance, dose-specific increase in nitric oxide production, dose-specific increase in vasodilation, reduced fat, increased muscle stamina, increased blood flow to muscles, increased blood flow to brain, decreased exercise/workout recovery time, increased exercise efficiency, increased alertness, pre-performance/workout treatment for stimulation of workout vigor (mental and physical) and enhanced performance, post-performance/workout supplement for muscle recovery, male/female virility enhancement, increased metabolic rate, increased workout volume, reduced feeling of effort during exercise, increased motivation to exercise, as drug or supplement delivery mechanism, as a nutrient delivery mechanism, oxygenated blood delivery, as a prevention and/or treatment of endothelial dysfunction, reduced stress and anxiety, as a sleep aid, reduced hangover after alcohol consumption, increased energy, enhanced heart health, enhanced respiratory efficiency, increased angiogenesis, as treatment for wound closure, enhanced food and beverage flavoring, improved skin and hair/coat in non-humans, improved skin and hair in humans, and enhanced matrix metalloproteinases proliferation.

### Claim 13

A method of extracting or isolating one or more galloylated procyanidins from a raw material that contains polyphenols, catechins, epicatechins, and galloylated epicatechins, the method comprising:
extracting the polyphenols, catechins, epicatechins, and galloylated epicatechins from the raw material using hot water at a temperature of about 80° C. to about 85° C. to provide an unrefined material;
passing the unrefined material through a mesh filter to provide a filtered material;
absorbing the filtered material with a macro-porous absorption resin;
eluting impurities from the filtered material absorbed to the resin using pure water;
eluting the material from the resin in ethanol and collecting an ethanol eluent fraction therefrom;
concentrating the ethanol eluent fraction and recovering a solvent using a vacuum system to provide a resulting material;
pasteurizing, sterilizing, and cooling the resulting material;
spray drying the material into a powder; and
sifting and v-blending the powder.

### Claim 14 (depends on 13)

The method of claim 13, wherein the raw material is selected from a group consisting of: green tea leaves, apples (peel on), apricots, pecans, pistachios, almonds and hazelnuts, cherries, peaches, blackberries, black grapes, strawberries, concord grapes, red grapes, cocoa beans, plums (black diamond raw with peel on), pears, Oolong tea, milk chocolate, fava beans, dark chocolate, cherries, cacao beans, broad beans (immature seeds), black tea, peanut skins, grape vine, blueberries and raspberries.

### Claim 15 (depends on 13)

The method of claim 13, wherein the one or more galloylated procyanidins have between about two (2) and about five (5) monomers.

### Claim 16 (depends on 13)

The method of claim 13, wherein the one or more galloylated procyanidins include isolated epicatechin-(4-8)-epicatechin-(4-8)-epicatechin-gallate, catechin trimer gallate, or combinations thereof.

### Claim 17

A method of extracting or isolating one or more galloylated procyanidins from a sample, comprising:
initially extracting polyphenols, catechins, epicatechins, and galloylated epicatechins from the sample using ethyl acetate;
further extracting the polyphenols, catechins, epicatechins, and galloylated epicatechins from the sample using water to provide a resulting material;
eluting the resulting material using resin and diluting the material with ethanol;
filtering the material using activated carbon;
concentrating the material;
spray drying the material into a powder; and
v-blending, sieving, and de-ironing the powder.