WO2021137926A1 - Composition de boisson caféinée améliorée - Google Patents

Composition de boisson caféinée améliorée Download PDF

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Publication number
WO2021137926A1
WO2021137926A1 PCT/US2020/058138 US2020058138W WO2021137926A1 WO 2021137926 A1 WO2021137926 A1 WO 2021137926A1 US 2020058138 W US2020058138 W US 2020058138W WO 2021137926 A1 WO2021137926 A1 WO 2021137926A1
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WO
WIPO (PCT)
Prior art keywords
theacrine
coffee
methylliberine
caffeine
caffeinated
Prior art date
Application number
PCT/US2020/058138
Other languages
English (en)
Inventor
Hector L. Lopez
Tim N. Ziegenfuss
Matthew TITLOW
Original Assignee
Ortho-Nutra, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ortho-Nutra, Llc filed Critical Ortho-Nutra, Llc
Priority to CN202080096737.1A priority Critical patent/CN115279197A/zh
Priority to BR112022013141A priority patent/BR112022013141A2/pt
Priority to CA3166354A priority patent/CA3166354A1/fr
Publication of WO2021137926A1 publication Critical patent/WO2021137926A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23F—COFFEE; TEA; THEIR SUBSTITUTES; MANUFACTURE, PREPARATION, OR INFUSION THEREOF
    • A23F5/00—Coffee; Coffee substitutes; Preparations thereof
    • A23F5/24—Extraction of coffee; Coffee extracts; Making instant coffee
    • A23F5/243—Liquid, semi-liquid or non-dried semi-solid coffee extract preparations; Coffee gels; Liquid coffee in solid capsules
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23F—COFFEE; TEA; THEIR SUBSTITUTES; MANUFACTURE, PREPARATION, OR INFUSION THEREOF
    • A23F5/00—Coffee; Coffee substitutes; Preparations thereof
    • A23F5/24—Extraction of coffee; Coffee extracts; Making instant coffee
    • A23F5/26—Extraction of water-soluble constituents
    • A23F5/267—Extraction of water-soluble constituents using additives, specific extraction media or specific coffee blends
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir

Definitions

  • the field of the invention is a caffeinated beverage supplemented with theacrine and methylliberine.
  • Tea and coffee are the most widely consumed products in the world. Tea and the different varieties of tea have been extensively studied. Many epidemiologic and preclinical studies suggest that drinking tea may reduce the risk of cancer and cardiovascular disease.
  • Theacrine, an alkaloid purine similar to caffeine is relatively rare and only found in a few varieties of tea (kucha tea, genus Camellia), the fruit cupuacu, and other plants related to coffee and cacao (genera Coffea and Theobroma), such as Coffea liberica, Coffea dewevrei, Coffea abeokutae and Theobroma grandiflorum.
  • 1,3, 7, 9 tetramethyluric acid was not studied until around 1975. However, it has been known of since about 1937, when it was detected in dry, decaffeinated Camellia sinensis tea leaves. At this time, the Camellia assamica var. kucha variety of tea is the primary source of naturally occurring theacrine and produces the chemical in higher concentrations than other known plants. Interestingly, theacrine has not been detected at all in more traditional teas strains. It is believed to be formed by methylation of caffeine and may be an intermediary in the production of liberine or other purines. Its natural function, if any, remains unknown.
  • Theacrine has garnered attention only relatively recently, and often only as a secondary consideration when analyzing other compounds. Some studies suggest it may have beneficial qualities, such as serving as an effective anti-oxidant, anti-inflammatory and may have anti-obesity properties. [0005] In the studies involving theacrine, beneficial effects may be at least partially attributable to an assortment of purine alkaloids and phenolic compounds. The more common tea-related purine alkaloids include caffeine, theobromine, theophyline and theacrine.
  • the major tea phenolic compounds are gallic acid and eight naturally occurring tea catechins, including (+)- catechin (C), (-)-epicatechin (EC), (+)-gallocatechin (GC), (-)-epigallocatechin (EGC), (-)- catechin gallate (CG), (-)-gallocatechin gallate (GCG), (-)-epicatechin gallate (ECG) and (-)- epigallocatechin gallate (EGCG).
  • the inventive subject includes an enhanced caffeinated beverage supplemented with an effective blend of theacrine and methylliberine.
  • the enhanced caffeinated beverage is a stimulating drink conferring an increase in mood, energy, alertness, focus, and/or motivation for the consumer (person consuming the enhanced caffeinated beverage), while not adversely increasing the person’s heart rate or blood pressure.
  • a caffeinated beverage composition is supplemented with methylliberine and theacrine.
  • the methylliberine and theacrine are in an effective synergistic combination imparting the desired mood, energy, alertness, focus, and/or motivation at increased levels relative to a caffeinated beverage alone as well as those experienced from a weight amount of methylliberine (e.g., 100 mg) that is greater than the total weight amount of effective blend of methylliberine and theacrine (e.g., 75 mg).
  • Embodiments of the contemplated subject matter include a caffeinated beverage composition supplemented with methylliberine and theacrine, wherein the caffeinated beverage composition includes a caffeinated drink having a caffeine content of between about 1 mg/oz to 65 mg/oz, theacrine in an amount of between about 1.5 mg/oz to 15 mg/oz, and methylliberine in an amount of between about 3.0 mg/oz to 30 mg/oz.
  • the caffeinated beverage composition includes a caffeinated drink having a caffeine content of between about 1 mg/oz to 65 mg/oz, theacrine in an amount of between about 1.5 mg/oz to 10 mg/oz, and methylliberine in an amount of between about 3.0 mg/oz to 20 mg/oz.
  • the caffeinated beverage composition includes a caffeinated drink having a caffeine content of between about 1 mg/oz to 65 mg/oz, theacrine in an amount of between about 1.5 mg/oz to 5 mg/oz, and methylliberine in an amount of between about 3.0 mg/oz to 10 mg/oz.
  • theacrine and methylliberine are present in a weight ratio of between about 1:1.5 to 1:2.75 or 1:1.5 to 1:3.0. In exemplary embodiments, the theacrine and methylliberine are present in a weight ratio of between about 1:1.5 to 1:2.75.
  • the caffeinated drink is brewed coffee, tea, a cola, or an energy drink.
  • the caffeinated drink is brewed coffee. More preferably, the brewed coffee is a non-espresso coffee having a caffeine content of between about 10 to 30 mg/oz, or the brewed coffee is an espresso coffee having a caffeine content of between about 30 to 65 mg/oz in a volume of not more than 3 ounces.
  • the caffeinated beverage upon consumption by a person increases mood, energy, alertness, motivation, and/or focus in the person compared to the caffeinated beverage alone or the caffeinated beverage supplemented only with methylliberine of between about 6 mg/oz or 12.5 mg/oz.
  • the caffeinated beverage does not adversely affect heart rate and/or blood pressure in the person.
  • the increased mood, energy, alertness, motivation, and/or focus in the person is experienced by the person up to about 5 hours after consumption of the caffeinated beverage composition.
  • an enhanced coffee beverage includes a coffee drink supplemented with methylliberine and theacrine, wherein the coffee drink has a caffeine content of between about 1 mg/oz to 65 mg/oz, and the theacrine is in an amount of between about 1.5 mg/oz to 15 mg/oz, 1.5 mg/oz to 10 mg/oz, or 1.5 mg/oz to 5.0 mg/oz, and the methylliberine is added in an amount of between about 3.0 mg/oz to 30 mg/oz, 3.0 mg/oz to 20.0 mg/oz, or 3 mg/oz to 15 mg/oz, and wherein the theacrine and the methylliberine are in a weight ratio of between about 1:1.5 to 1:2.75 or 1:1.5 to 1:3.0.
  • Additional embodiments include a method of preparing an enhanced caffeinated beverage, including adding theacrine and methylliberine to a caffeinated drink, wherein the theacrine is added in an amount of between about 1.5 mg/oz to 15 mg/oz, 1.5 mg/oz to 10 mg/oz, or 1.5 mg/oz to 5.0 mg/oz, and the methylliberine is added in an amount of between about 3.0 mg/oz to 30 mg/oz, 3.0 mg/oz to 20.0 mg/oz, or 3 mg/oz to 15 mg/oz.
  • the method of preparing an enhanced caffeinated beverage includes a caffeinated drink selected from a brewed coffee, a tea, an energy drink, or a cola.
  • the method of preparing an enhanced caffeinated beverage includes a brewed coffee wherein the adding of the theacrine and methylliberine are added to coffee grounds prior to brewing the brewed coffee or the theacrine and methylliberine are added to the brewed coffee.
  • the brewed coffee includes non-espresso or espresso brewed coffees, and/or the brewed coffee may be hot brewed or cold brewed.
  • FIG. 1 depicts, in one embodiment, a molecular diagram of theacrine in accordance with the principles of the invention.
  • FIG. 2 depicts, in one embodiment, a graph of results of a trial showing perceived energy on a Visual Analogue Scale (VAS) scale (0 to 10 cm) at 1, 2 and 3 hours after administration of theacrine or placebo.
  • VAS Visual Analogue Scale
  • FIG. 3 depicts, in one embodiment, a graph of results of a trial showing perceived fatigue on a VAS scale (0 to 10 cm) at 0 minutes and 60 minutes after administration of theacrine or placebo.
  • FIG. 4 depicts, in one embodiment, a graph of results of a trial showing systolic blood pressure at various time intervals after administration of theacrine or placebo.
  • FIG. 5 depicts, in one embodiment, a graph of results of a trial showing diastolic blood pressure at various time intervals after administration of theacrine or placebo.
  • FIG. 6 shows, in one embodiment, the results of a 7 day repeated dose study of 200 mg theacrine relative to baseline of fatigue, anxiety and libido at various intervals after dosages (at 0 hr, 1 hr, 4 hr, 6 hr; bars left to right for each measured category).
  • FIG. 7 shows, in one embodiment, the results of a 7 day repeated dose study of 200 mg theacrine relative to baseline of energy, motivation to exercise, and concentration at various intervals after dosages (at 0 hr, 1 hr, 4 hr, 6 hr; bars left to right for each measured category).
  • FIG. 8(A) depicts, in one embodiment, individual plasma concentrations of theacrine after single oral dose of theacrine 25 mg.
  • FIG. 8(B) depicts, in one embodiment, individual plasma concentrations of theacrine after single oral dose of theacrine 125 mg.
  • FIG. 8(C) depicts, in one embodiment, individual plasma concentrations of theacrine after single oral dose of theacrine 125 mg plus caffeine 150 mg.
  • FIG. 9 depicts, in one embodiment, Forest plot illustrating the probability of interaction magnitude between theacrine and caffeine using 90% confidence intervals about the geometric mean ratio of the observed pharmacokinetic parameters following a single theacrine dose (
  • FIG. 10(A) depicts, in one embodiment, individual plasma concentrations of caffeine after single oral dose of caffeine 150 mg.
  • FIG. 10(B) depicts, in one embodiment, individual plasma concentrations of caffeine after single oral dose of theacrine 125 mg plus caffeine 150 mg.
  • FIG. 11 depicts, in one embodiment, Forest plot illustrating the probability of interaction magnitude between caffeine and theacrine using 90% confidence intervals about the geometric mean ratio of the observed pharmacokinetic parameters following a single caffeine dose (150 mg) alone or in combination with theacrine (125 mg).
  • FIG. 12(A) depicts, in one embodiment, mean values in heart rate after single dose theacrine 25 mg (- ⁇ -), theacrine 125 mg (- ⁇ - ), caffeine 150 mg (- ⁇ -), or theacrine 125 mg plus caffeine 150 mg (- ⁇ -).
  • FIG. 12(B) depicts, in one embodiment, mean values in systolic blood pressure after single dose theacrine 25 mg (- ⁇ -) theacrine 125 mg (- ⁇ - ), caffeine 150 mg (- ⁇ -), or theacrine 125 mg plus caffeine 150 mg (-A-).
  • FIG. 12(C) depicts, in one embodiment, mean values in diastolic blood pressure after single dose theacrine 25 mg (- ⁇ -), theacrine 125 mg (- ⁇ ), caffeine 150 mg (- ⁇ -), or theacrine 125 mg plus caffeine 150 mg (-A-).
  • FIG. 12(D) depicts, in one embodiment, mean values in rate pressure product after single dose theacrine 25 mg (- ⁇ -), theacrine 125 mg (- ⁇ - ), caffeine 150 mg (- ⁇ -), or theacrine 125 mg plus caffeine 150 mg (- ⁇ -).
  • FIG. 13(A) depicts, in one embodiment, a graph of results of a trial showing the change (Delta) in perceived mood as measured using a VAS scale before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee caffeinated coffee
  • Coffee with 50 mg methylliberine Dynamine
  • Coffee with 50 mg Dynamine and 25 mg theacrine TriaCrine
  • Coffee with 100 mg Dynamine as indicated.
  • FIG. 13(B) depicts, in one embodiment, a graph of results of a trial showing the change (Delta) in perceived energy as measured using a VAS scale before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee caffeinated coffee
  • Coffee with 50 mg methylliberine Dynamine
  • Coffee with 50 mg Dynamine and 25 mg theacrine TriaCrine
  • Coffee with 100 mg Dynamine as indicated.
  • FIG. 13(C) depicts, in one embodiment, a graph of results of a trial showing the change (Delta) in perceived motivation as measured using a VAS scale before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee caffeinated coffee
  • Coffee with 50 mg methylliberine Dynamine
  • Coffee with 50 mg Dynamine and 25 mg theacrine TriaCrine
  • Coffee with 100 mg Dynamine as indicated.
  • FIG. 13(D) depicts, in one embodiment, a graph of results of a trial showing the change (Delta) in perceived alertness as measured using a VAS scale before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee caffeinated coffee
  • Coffee with 50 mg methylliberine Dynamine
  • Coffee with 50 mg Dynamine and 25 mg theacrine TriaCrine
  • Coffee with 100 mg Dynamine as indicated.
  • FIG. 13(E) depicts, in one embodiment, a graph of results of a trial showing the change (Delta) in perceived fatigue as measured using a VAS scale before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee caffeinated coffee
  • Coffee with 50 mg methylliberine Dynamine
  • Coffee with 50 mg Dynamine and 25 mg theacrine TriaCrine
  • Coffee with 100 mg Dynamine as indicated.
  • FIG. 13(F) depicts, in one embodiment, a graph of results of a trial showing the change (Delta) in perceived focus as measured using a VAS scale before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee caffeinated coffee
  • Coffee with 50 mg methylliberine Dynamine
  • Coffee with 50 mg Dynamine and 25 mg theacrine TriaCrine
  • Coffee with 100 mg Dynamine as indicated.
  • 13(G) depicts, in one embodiment, a graph of results of a trial showing the change (Delta) in perceived creativity as measured using a VAS scale before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee caffeinated coffee
  • Coffee with 50 mg methylliberine Dynamine
  • Coffee with 50 mg Dynamine and 25 mg theacrine TriaCrine
  • Coffee with 100 mg Dynamine as indicated.
  • FIG. 13(H) depicts, in one embodiment, a graph of results of a trial showing the change (Delta) in perceived concentration as measured using a VAS scale before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee caffeinated coffee
  • Coffee with 50 mg methylliberine Dynamine
  • Coffee with 50 mg Dynamine and 25 mg theacrine TriaCrine
  • Coffee with 100 mg Dynamine as indicated.
  • FIG. 14(A) depicts, in one embodiment, a graph of results of a trial showing the change (Delta) in mean values of systolic blood pressure (BP) before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee Coffee with 50 mg methylliberine
  • Dynamine Coffee with 50 mg Dynamine and 25 mg theacrine
  • Coffee with 100 mg Dynamine as indicated.
  • FIG. 14(B) depicts, in one embodiment, a graph of results of a trial showing the change (Delta) in mean values of diastolic blood pressure (BP) before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee Coffee with 50 mg methylliberine
  • Dynamine Coffee with 50 mg Dynamine and 25 mg theacrine
  • Coffee with 100 mg Dynamine as indicated.
  • FIG. 14(C) in one embodiment, a graph of results of a trial showing the change (Delta) in mean values of heart rate before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee caffeinated coffee
  • Coffee with 50 mg methylliberine Dynamine
  • Coffee with 50 mg Dynamine and 25 mg theacrine TeaCrine
  • Coffee with 100 mg Dynamine as indicated.
  • FIG. 14(D) in one embodiment, a graph of results of a trial showing the change (Delta) in mean values of rate pressure product before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee caffeinated coffee
  • Coffee with 50 mg methylliberine Dynamine
  • Coffee with 50 mg Dynamine and 25 mg theacrine TeaCrine
  • Coffee with 100 mg Dynamine as indicated.
  • FIG. 14(E) in one embodiment, a graph of results of a trial showing the change (Delta) in mean values of mean arterial pressure before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee caffeinated coffee
  • Coffee with 50 mg methylliberine Dynamine
  • Coffee with 50 mg Dynamine and 25 mg theacrine TeaCrine
  • Coffee with 100 mg Dynamine as indicated.
  • FIG. 14(F) in one embodiment, a graph of results of a trial showing the change (Delta) in mean values of pulse pressure before and 180 minutes after consumption of a decaffeinated coffee beverage (DECAFF), caffeinated coffee (Coffee), Coffee with 50 mg methylliberine (Dynamine), Coffee with 50 mg Dynamine and 25 mg theacrine (TeaCrine), or Coffee with 100 mg Dynamine, as indicated.
  • DECAFF decaffeinated coffee beverage
  • Coffee caffeinated coffee
  • Coffee with 50 mg methylliberine Dynamine
  • Coffee with 50 mg Dynamine and 25 mg theacrine TeaCrine
  • Coffee with 100 mg Dynamine as indicated.
  • Theacrine also known as 1, 3,7,9- tetramethyluric acid, Temurin, Temorine, Tetramethyluric acid, Tetr am ethyl uric acid and l,3,7,9-tetramethylpurine-2,6,8-trione.
  • Theacrine may be produced synthetically or may be isolated from a natural source.
  • Theacrine isolated from a natural source may be purified to 95% or greater. Optionally, less purification may be used such that theacrine accounts for 50%, or even less, of the material.
  • theacrine isolated from a natural source which may include other congeners of theacrine typically found in theacrine isolates.
  • MLL methylliberine
  • a caffeinated beverage e.g., brewed caffeinated coffee
  • results in an enhanced caffeinated beverage providing increased mood (e.g., positive mood), energy, motivation, alertness, focus, and/or decreased fatigue relative to a caffeinated drink supplemented with methylliberine alone at even greater amounts (e.g., 100 mg MLL) than the effective blend of methylliberine and theacrine (e.g., at a total of 75 mg).
  • methylliberine and theacrine in a caffeinated beverage confers improved and desirable effects while tempering physiological side effects common to these stimulants.
  • an effective blend of methylliberine and theacrine in caffeinated did not adversely affect blood pressure or heart rate.
  • a caffeinated beverage is any consumable drink having caffeine.
  • caffeinated drinks include coffee, tea (e.g., black or green), a cola drink (e.g, Coca- Cola®, Pepsi®, etc.), or an energy drink (e.g., Red Bull®, Monster®, or Wired®).
  • the energy drink is a non-coffee energy drink and/or a non-cola energy drink.
  • a coffee drink refers to any type of coffee brewed from water and coffee grounds.
  • the coffee drink may be hot brewed or cold brewed.
  • the coffee drink may be a non- espresso coffee or an espresso brewed coffee.
  • the coffee drink may be brewed using any suitable method. Examples of hot or cold coffee brewing methods include drip brew, French press, espresso brewing, modular non-espresso brewing using pods (e.g., Keurig®), or modular espresso brewing (e.g., Nespresso®).
  • brewing methods vary by size of coffee grounds, the water temperature passing over the grounds, and/or the pressure of the water passing over the grounds.
  • the contemplated caffeinated beverage supplemented with an effective blend of theacrine and methylliberine is a stimulating drink without negative physiological effects (e.g., increased heart rate or blood pressure) made of a synergistic combination of theacrine and methylliberine added to the caffeinated drink.
  • the synergistic combination is an effective blend in which the theacrine and methylliberine are present in a weight ratio of between about 1:1.5 to 1:3.0 resulting in the supplemented caffeinated beverage having the advantageous and desired effects.
  • the effective blend of theacrine and methylliberine in the enhanced caffeinated beverage is in a weight ratio of between about 1 : 1.5 to 1 :2.75 or 1 : 1.5 to 1:3.0, and includes theacrine in an amount in milligrams per ounce (mg/oz) between about 1.5 mg/oz to 15 mg/oz, (0.05 mg/ml to 0.51 mg/ml) and methylliberine in an amount of between about 3.0 mg/oz to 30 mg/oz (0.10 mg/ml to 1.02 mg/ml).
  • the disclosed effective blend of theacrine and methylliberine includes theacrine at an amount of between about 1.5, 1.6, 1.7, 1.8, 1.9. 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8,
  • the effective blend of theacrine and methylliberine includes theacrine at an amount of between about 2 mg/oz to 15 mg/oz, 2 mg/oz to 12 mg/oz, 2 mg/oz to 10 mg/oz, 2 mg/oz to 7 mg/oz, or 2 mg/oz to 5 mg/oz. More typically, the caffeinated drink is supplemented with theacrine at an amount of between about 2.5 mg/oz to 4.0 mg/oz.
  • the caffeinated drink is supplemented with theacrine at an amount of between about 2.75 mg/oz to 3.5 mg/oz.
  • the disclosed effective blend of theacrine and methylliberine includes methylliberine in an amount of between about 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2,
  • the effective blend of theacrine and methylliberine includes methylliberine at an amount of between about 3 mg/oz to 25 mg/oz, 3 mg/oz to 20 mg/oz, 3 mg/oz to 19 mg/oz, 3 mg/oz to 18 mg/oz, 3 mg/oz to 17 mg/oz, 3 mg/oz to 16 mg/oz, 3 mg/oz to 15 mg/oz, 3 mg/oz to 14 mg/oz, 3 mg/oz to 13 mg/oz, 3 mg/oz to 12 mg/oz, 3 mg/oz to 11 mg/oz, 3 mg/oz to 10 mg/oz, 3 mg/oz to 9 mg/oz, or 3 mg/oz to 8 mg/oz.
  • the caffeinated drink is supplemented with methylliberine at an amount of between about 5 mg/oz to 20 mg/oz, 5 mg/oz to 15 mg/oz, 5 mg/oz to 10 mg/oz. Most typically, the caffeinated drink is supplemented with methylliberine at an amount of between about 6.0 mg/oz to 8.0 mg/oz. For example, the caffeinated drink may be supplemented with methylliberine at an amount of between about 6.0 mg/oz to 7 mg/oz.
  • the enhanced caffeinated drink e.g., coffee, tea, cola, or an energy drink
  • the caffeinated drink has a caffeine content of between about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65 mg/oz.
  • the caffeinated drink has a caffeine content of between about 10 mg/oz to 65 mg/oz, 15 mg/oz to 65 mg/oz, 20 mg/oz to 65 mg/oz. More typically, the caffeinated drink has a caffeine content of between about 10 mg/oz to 25 mg/oz.
  • an enhanced caffeinated beverage is a coffee drink supplemented with the disclosed effective blend of theacrine and methylliberine.
  • the coffee drink may be hot or cold brewed and may be a non-espresso brewed coffee or an espresso brewed coffee having a caffeine content of between about 1 mg/oz to 65 mg/oz.
  • the caffeine content is more typically about 40 to 65 mg/oz for a volume of not more than 3 ounces.
  • the caffeine content is about 40 to 65 mg/oz with a total weight amount of both theacrine and methylliberine of about 15 to 30 mg/oz, e.g., 15-20 mg/oz for a 3.0 oz espresso or about 20-30 mg/oz for a 2 oz espresso.
  • An espresso drink is typically not more than 3 oz and may also be 2 oz.
  • the caffeine content is more typically about 10 to 30 mg/oz, 10 to 25 mg/oz, 10 to 20 mg/oz, or 15 to 25 mg/oz.
  • the coffee drink is supplemented with the disclosed effective blend of theacrine in an amount of between about 1.5 mg/oz to 15 mg/oz and methylliberine in an amount of between about 3.0 mg/oz to 30 mg/oz. More preferably, the coffee drink is supplemented with the disclosed effective blend of theacrine in an amount of between about 1.5 mg/oz to 15 mg/oz, 1.5 mg/oz to 10 mg/oz, or 1.5 mg/oz to 5.0 mg/oz, and the methylliberine is added in an amount of between about 3.0 mg/oz to 30 mg/oz, 3.0 mg/oz to 20.0 mg/oz, or 3 mg/oz to 15 mg/oz.
  • the coffee drink is supplemented with the disclosed effective blend of theacrine in an amount of between about 1.5 mg/oz to 15 mg/oz and methylliberine in an amount of between about 3.0 mg/oz to 30 mg/oz, wherein the theacrine and methylliberine are present in a weight ratio of between about 1:1.5 to 1:2.75.
  • the effective blend disclosed herein of theacrine and methylliberine refers to the ratio of theacrine and methylliberine; however, the addition of theacrine and methylliberine to the brewed coffee may be carried out sequentially.
  • methods for preparing the enhanced coffee beverage include supplementing the brewed coffee or coffee grounds with theacrine and methylliberine using any suitable method.
  • theacrine and methylliberine are added either sequentially or concurrently to brewed coffee.
  • the theacrine and methylliberine may be added to a single serving of brewed coffee or may be added to a large stock of brewed coffee that is then served or packaged into smaller volumes.
  • one or both of the theacrine and methylliberine are added to the coffee grounds prior to the brewing process.
  • results of a trial of volunteers consuming the enhance coffee beverage with 50 mg methylliberine and 25 mg theacrine showed increased mood (FIG. 13A), energy (FIG. 13B), motivation (FIG. 13C), alertness (FIG. 13D), decreased fatigue (FIG. 13E), and increased focus (FIG. 13F) as measured using a visual analogue scale (VAS) assessment as disclosed herein, compared to the reported effects after consumption of a decaffeinated coffee beverage, caffeinated coffee, coffee with 50 mg methylliberine, or coffee with 100 mg methylliberine. Accordingly, as shown in FIGS.
  • VAS visual analogue scale
  • a caffeinated beverage e.g., coffee
  • the effective blend of theacrine and methylliberine upon consumption by a person, increases mood, energy, alertness, motivation, and/or focus in the person compared to the caffeinated beverage alone or the caffeinated beverage supplemented only with methylliberine at 50 mg alone or 100 mg alone, or about 6 mg/oz or 12.5 mg/oz, respectively.
  • the increase in mood refers to an increase in a positive mood in which the person experiences increased content.
  • the effects on mood, energy, alertness, focus, motivation, and/or decreased fatigue are observed at least as soon as 60 minutes after consumption of the enhance coffee beverage and may be experienced up to 5 hours (i.e., 300 minutes) after consumption.
  • the effects on increased mood, energy, alertness, focus, motivation, and/or decreased fatigue are experienced at least as soon as 60 minutes from consumption up to 90 minutes, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours after consumption.
  • the effects on increased mood, energy, alertness, focus, motivation, and/or decreased fatigue are experienced at least as soon as 60 minutes from consumption up to 4 hours.
  • the effects on increased mood, energy, alertness, focus, motivation, and/or decreased fatigue are experienced at least as soon as 60 minutes from consumption up to 3 hours (180 minutes).
  • blood pressure systolic and diabolic
  • heart rate e.g., heart rate
  • rate pressure product mean arterial pressure
  • pulse pressure e.g., pulse pressure
  • theacrine may be combined with other chemical compounds to provide a plurality of positive effects on a human or other animal.
  • various physiological effects may be selected for.
  • the compositions may provide primarily a single benefit, or may provide multiple benefits simultaneously.
  • theacrine may be used at lower dosage levels and/or in conjunction with compounds that modulate or antagonize its activity.
  • Such compositions may induce an improved mood, higher energy, a reduction in fatigue, increased focus, increased concentration, increased mobility, decreased appetite, and increased stamina.
  • An advantage of using the invention may be the reduced likelihood that a person develops a tolerance to chemical compositions in accordance with the principles of the invention. That is, a person may not become desensitized to the effects induced.
  • theacrine may be used at higher dosage levels and/or with synergistic compounds. These compositions may increase a person's basal/resting metabolic rate, increase thermogenesis, decrease appetite, enhance cognitive performance, increase Alpha wave brain activity, and/or induce euphoria. Without being bound by theory, the inventors believe that at higher dosage levels, theacrine may be noradrenergic and dopaminergic, and may exhibit increased adenosine receptor inhibition.
  • theacrine may be combined with ephedrine, caffeine, salicylic acid or the like. These may be used to either modulate the more sedative effects of theacrine or optionally to interact synergistically with the more stimulating effects of theacrine.
  • theacrine may be combined with caffeine in order to modulate the excessive stimulatory effects of caffeine, thereby stabilizing heart rate and other metabolic activity. That is, a combination of theacrine and caffeine may result in a composition that imparts the increased focus and energy induced by caffeine, but without the higher heart rate and blood pressure due to modulation of caffeine by theacrine. Thus the combination may result in heightened awareness and calmness without the jitters caffeine may cause.
  • Theacrine and caffeine administered in combination has unexpected effects. Indeed, it has been unexpectedly found that a combination of theacrine and caffeine administered to human subjects results in increased levels of focus, concentration and energy as measured by 100 mm VAS scales while also decreasing measures of anxiety, irritability or feelings of overstimulation. Such decrease in anxiety, irritability, jitters and/or feelings of overstimulation is reflected by patients on standardized 100 mm VAS at durations of 30 minutes, 60 minutes, 120 minutes and 180 minutes as compared with administration of caffeine alone. The combination also exhibits a prolonged duration of action in increased energy, focus and/or concentration as compared to either caffeine or theacrine alone.
  • theacrine also has unexpected effects on the development of tolerance and habituation of caffeine.
  • a fourteen day study of repetitive dosing of theacrine and caffeine it was found that the subjects maintained heightened psychometric indices of energy, focus, concentration, motivation to exercise, motivation to accomplish and finished tasks, and improved mood at Day 14 as compared to caffeine alone, and absolute levels of energy and motivation were greater than with theacrine alone.
  • Those taking theacrine alone still maintained elevated subjective energy, focus, concentration, motivation to exercise, motivation to accomplish and finish tasks, sexual desire and improved mood with decreased anxiety as compared to Day 1.
  • Subjects taking caffeine alone saw decreasing levels of energy, focus and concentration by Day 5 of the study and had increased anxiety scores throughout the study.
  • theacrine may be combined with one or more bioavailability enhancers, including for example bioperine, pipeline, black pepper, bergamottin, dihydroxybergamottin (CYP3 A4 inhibitors), flavonoids (including hesperidin, naringin, tangeritin, quercetin and nobiletin both in isolation and in combination), pterostilbenes, fisetin, nanoencapsulation, microencapsulation, liposomes and/or phytosomes.
  • bioavailability enhancers including for example bioperine, pipeline, black pepper, bergamottin, dihydroxybergamottin (CYP3 A4 inhibitors), flavonoids (including hesperidin, naringin, tangeritin, quercetin and nobiletin both in isolation and in combination), pterostilbenes, fisetin, nanoencapsulation, microencapsulation, liposomes and/or phytosomes.
  • which enhancers are combined with theacrine may
  • theacrine may be introduced using one or more delivery methods, including, for example transdermal patches and/or creams, ready to mix powders, intravenous methods, capsules, tablets, liquid (including liquids for mixing with other beverages), softgels, shot format, and/or cosmetic applications including soaps, lotions and shampoos.
  • delivery methods including, for example transdermal patches and/or creams, ready to mix powders, intravenous methods, capsules, tablets, liquid (including liquids for mixing with other beverages), softgels, shot format, and/or cosmetic applications including soaps, lotions and shampoos.
  • Theacrine's anti-inflammatory qualities may be desired for a variety of topical applications.
  • theacrine may be used to provide sports performance enhancers that may reduce fatigue, improve mobility, and improve alertness.
  • theacrine may be used as a topical agent for incorporation into body creams or lotions to produce a cream or lotion for lightening skin, firming skin, and/or improving skin elasticity.
  • a theacrine topical agent may also be used to promote localized transdermal fat loss.
  • Theacrine may also be used in a cream or lotion to promote localized enhanced metabolism and/or enhanced thermogenesis.
  • theacrine may be combined with one or more of an analgesic, for example ibuprofen or salicylic acid, anti-inflammatory agents, salicin, fish oil (omega-3 fatty acids and specialized, small lipid pro-resolving derivatives), tart cherry, krill oil, astaxanthin, proteolytic enzymes, glucosamine sulfate, chondroitin sulfate, MSM (methyl sulfonylmethane), SAMe (S-adenosylmethionine), ASU (avocado-soybean unsapponifiable fraction), cetyl myristoleate, Dolichos falcate and/or triterpenoids.
  • an analgesic for example ibuprofen or salicylic acid
  • anti-inflammatory agents for example ibuprofen or salicylic acid
  • salicin fish oil (omega-3 fatty acids and specialized, small lipid pro-resolving derivatives)
  • Theacrine itself can reduce biomarkers of inflammation in humans in response to acute inflammatory stressors (e.g., intense exercise) or chronic consumption.
  • Theacrine is shown to decrease C-reactive protein (CRP), Erythrocyte sedimentation rate (ESR), interieukin-6 (IL-6) and TNF- alpha.
  • CRP C-reactive protein
  • ESR Erythrocyte sedimentation rate
  • IL-6 interieukin-6
  • TNF- alpha TNF- alpha
  • theacrine may be combined with extracts from one or more of Acacia catechu, Andrographis paniculata, Scutalleria baicalensis, agmatine sulfate, Stinging Nettle, Sea Buckthorn, curcumin, Cissus Quadrilangularis, Boswellia Serrata, Wasabia japonica (wasabi extract for Tea Tree Oil), Emu Oil, Arnica, Mangifera indica L. (Anacardiaceae), Lagenaria breviflora, and/or Zingiber officinale (ginger & gingerols/shogaols).
  • Such a combination may be used in, for example, methods of augmenting and enhancing pain modulation, and controlling the inflammatory response.
  • theacrine may be combined with one or more metabolic enhancers including Hoodia gordonii, caffeine, yohimbine, synephrine, theobromine, flavonoids, flavanone glycosides such as naringin and hesperidin, tocopherol s, theophylline, alpha-yohimbine, conjugated linoleic acid (CLA), octopamine, evodiamine, passion flower, red pepper, cayenne, raspberry ketone, guggul, green tea, guar ana, kola nut, any beta- phenethylamines, Acacia rigidula, and/or forskolin (Coleus forskohlli).
  • one or more metabolic enhancers including Hoodia gordonii, caffeine, yohimbine, synephrine, theobromine, flavonoids, flavanone glycosides such as naringin and hesperidin, tocopherol s,
  • Such a combination may be used in, for example, methods of enhancing 1) therm ogenesis/fat and carbohydrate metabolism; 2) fat loss, weight management and improving body composition (loss of body fat, while retaining or sparing lean body mass/fat free mass/muscle); and/or 3) appetite control/appetite modulation.
  • Theobromine is used by some for improvement of breathing or a subjective feeling of improved breathing, but is also known to increase feelings of anxiety, jitters and an elevated heart rate in some subjects.
  • a combination of theobromine and theacrine retains the beneficial effects while reducing the unwanted anxiety, jitters and/or elevated heart rate effects.
  • theacrine may be combined with anti-fatigue, focusing and/or energy enhancing ingredients including caffeine, theobromine, theophylline, synephrine, yohimbine, rhodiola, ashwagandha, ginseng, Ginkgo biloba, Siberian ginseng, astragalus, licorice, green tea, reishi, dehydroepiandrosterone (DHEA), pregnenolone, tyrosine, N-acetyl-tyrosine, glucuronolactone, taurine, choline, CDP-choline, alpha-GPC, acetyl-L- camitine, 5-hydroxytryptophan, tryptophan, any beta-phenethylamines, Sceletium tortuosum (and Mesembrine alkaloids), Dendrobium sp., Acacia rigidula, PQQ (Pyroloquinoline quin
  • Such a combination may be used in, for example, methods for enhancing cognitive function, including focus, concentration, sustained attention, working memory, choice and non-choice reaction time, executive function, verbal and non-verbal learning, visuospatial memory and verbal fluency.
  • theacrine may be combined with a nutritional cholinergic ingredient such as 2-(dimethylamino)ethanol (DMAE), DMAE bitartrate, choline bitartrate, alpha-GPC (alpha-glycerophosphorylcholine), Huperzine A, CDP choline, or combinations thereof.
  • DMAE 2-(dimethylamino)ethanol
  • DMAE bitartrate DMAE bitartrate
  • choline bitartrate choline bitartrate
  • alpha-GPC alpha-glycerophosphorylcholine
  • Huperzine A CDP choline
  • any of the above combinations may be used with an isomer of, congener of, derivative of and/or a metabolite of theacrine such as, for example, liberine or methylliberine.
  • suitable examples include methylated theacrine, nitrate salts of theacrine, oxidized theacrine, reduced theacrine and/or theacrine salts.
  • Agglomerated theacrine, microencapsulated theacrine, liposomal theacrine, esterified theacrine, theacrine glycerides, and mixtures of theacrine with propylene glycol, lauroyl Macrogol, polyethylene glycol, theacrine derivatives, and/or theacrine co-crystallization products may also be used in accordance with the principles of the invention.
  • theacrine salts including citrate, salicylate, malate, tartrate, fumarate, succinate, nitrate, sulfate, phosphate and the like, or PEG-ylated (Macrogol) preparations may increase the functional efficacy of the theacrine.
  • congeners of theacrine for example catechins and other flavonoids, may be used an isolated, either independently or in combination with theacrine-based compositions.
  • the dosage of theacrine may range from about 5 mg to about 850 mg. In another embodiment, the range may be from about 65 mg to about 300 mg. In relation to the weight of the human subject, in one embodiment the dosage may be expressed as about 0.75 mg/kg of body weight to about 3 mg/kg of body weight. In initial trials the human ED90 appears to be about 1 mg/kg to about 3 mg/kg.
  • the theacrine may be administered with caffeine.
  • the ratio of caffeine to theacrine, weight to weight may range from about 0.5: 1 to about 50: 1, and in another embodiment, from about 1 : 1 to about 10: 1, and in a further embodiment, from about 2: 1 to about 4: 1.
  • the theacrine may be administered in an amount of about 5 mg to about 800 mg with caffeine amounts ranging from about 25 mg to about 650 mg.
  • the theacrine may be administered in an amount of about 5 mg to about 650 mg with the caffeine, and in other embodiments may be any amount in that range.
  • Such administration provides an increase, as measured by 100 mm VAS scales, in at least one of focus, concentration and energy, while also providing a decrease in at least one of anxiety, irritability, and feelings of overstimulation.
  • Recommended dosages expressed in terms of amount per body weight can range from about 0.75 mg/kg to about 3 mg/kg of theacrine when administered in combination with caffeine, although theacrine may be administered in the ranges described above up to about 850 mg regardless of whether it is administered in combination with caffeine.
  • the invention may be used for the treatment of a variety of conditions, such as improvement of mood, energy, focus, or concentration.
  • the invention may also promote a reduced appetite, reduce the perceived exertion from exercise, decrease the discomfort associated with intense exercise, and may also improve sexual desire.
  • inventive subject matter provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
  • the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
  • subjects included subjects who were pregnant or lactating, subjects with a history of hepatorenal, musculoskeletal, autoimmune, or neurologic disease, diabetes, thyroid disease, adrenal disease, hypogonadism, inborn error of metabolism, personal history of heart disease, high blood pressure (systolic >140 mm Hg & diastolic >90 mm Hg), psychiatric disorders, cancer, benign prostate hypertrophy, caffeine sensitivity, gastric ulcer, reflux disease, or any other medical condition deemed exclusionary by the medical staff, subjects currently taking thyroid, hyperiipidemic, hypoglycemic, anti-hypertensive, anti-coagulant medications or OTC products containing pseudoephedrine or other stimulants, subjects who had used any weight-loss supplements within 30-days prior to the study, subjects who had gained or lost more than 10 lbs within the past 30 days, subjects who drank more than one cup of percolated coffee or 2 cups of tea per day, subjects who smoked or had quit
  • Example 1 Statistical Analyses for Example 1. Descriptive statistics (mean, median, SD, 95% CIs) were used to quantify subjects physical characteristics. RM ANOVA, as well analyses of co-variance (ANCOVA), using baseline scores as the co-variate (respectively), were used to analyze between trial differences. Alpha was set to 0.05 (P.ltoreq.0.05) for statistical significance, and ⁇ 0.10 for trends. Effect sizes were also calculated.
  • subjects were randomly assigned to receive their respective supplement/placebo. Each subject ingested the sponsor recommended dosage of their respective supplement (1 capsule prior to schedule of assessments). Supplements were prepared in capsule form and packaged in coded generic containers for double-blind administration.
  • FIG. 2 shows that individuals who were administered theacrine reported higher levels of energy at each time increment measured.
  • FIG. 3 shows that while individuals given the placebo reported higher fatigue at 60 minutes after administration, those administered theacrine reported lower levels of fatigue.
  • FIGS. 4 and 5 show that no substantial change in systemic hemodynamics occurred.
  • Example 2 Theacrine pharmacokinetics in humans has not been systematically characterized. Therefore, one purpose of this study, among others, was to determine theacrine pharmacokinetics and dose-linearity following oral administration in humans. Another purpose of this study is to determine whether or not caffeine alters theacrine pharmacokinetics and/or pharmacodynamics, when both ingredients are ingested together.
  • Test Visit Procedures Each study day, subjects reported to the lab between 6:00 and 7:00 am after a 10-hour fast and abstinence from beverages, drugs, or supplements containing alcohol or caffeine (72-hours) and strenuous physical exercise (24-hours). A catheter was inserted into the forearm vein for blood sampling. Duplicate measurements of resting heart rate and blood pressure were taken pre-dose and prior to each timed blood sample. In addition, respiratory rate was counted in one minute and body temperature was measured using an ear scanning thermometer (dual readings taken at each time). At approximately 8:00 am, each subject received a single oral dose of a theacrine, caffeine, or combined theacrine-caffeine composition accompanied by water.
  • Blood samples at 0 minute (5 samples obtained for baseline prior to administration of the oral compositions), 15 minutes, 30 minutes, 60 minutes, and 90 minutes, and 2, 4, 6, 8, and 24 hours post-administration. Collected samples were processed and stored in multiple aliquots (.about.500 pL, -70.degree. C.) until analyzed for theacrine, caffeine, and paraxanthine using LC-MS/MS.
  • Food Processor SQL version 9.9; ESHA Research, Salem, Oreg.
  • standardized meals meal replacement food bars [Clif "Builder's 20 g Protein Bar”] and ready-to- drink shakes [Orgain Organic NutritionTM]) were provided to the subjects after sample collection at hour 2 and hour 6 (one shake and one-half bar at each time). Subjects were also provided with adequate meal replacement bars and shakes to consume following the 8 hour sample collection, (during their time outside the lab).
  • Each bar contained 280 calories, 10 grams of fat, 29 grams of carbohydrate, and 20 grams of protein.
  • Each shake contained 250 calories, 7 grams of fat, 32 grams of carbohydrate, and 16 grams of protein.
  • caffeine co-administration significantly increased both mean theacrine exposure parameters C max, (38.6 ⁇ 16.6 versus 25.6 ⁇ 5.5 ng/mL) and AUC (1.2 ⁇ 1.1 versus 0.74 ⁇ 0.31 hr* ⁇ g/mL/mg) as well as geometric mean ratios (1.1 ⁇ 0.06 and 1.1 ⁇ 0.03) (Table 2).
  • caffeine decreased both theacrine oral clearance (CL/F, 1.6 ⁇ 0.49 versus 1.2. ⁇ 0.56 L/hr) and oral volume of distribution (Vd/F, 50.5 ⁇ 0.49 versus 35.4 ⁇ 12.4 L) by approximately 30%.
  • theacrine exposure (AUC) was consistently higher in Subject 8 than all other subjects in all treatment arms.
  • caffeine pharmacokinetics in Subject 8 was similar to the other seven subjects. Caffeine pharmacokinetics is similar following caffeine alone or caffeine plus theacrine co-ingestion (FIGS. 10 and 11 and Table 2). Likewise, theacrine co-ingestion did not alter paraxanthine exposure parameters suggesting caffeine metabolism was unaffected by theacrine (Table 3).
  • CYP1 A2 polymorphism located in the common promoter region between CYPJA] and CYP1 A2, significantly associated with caffeine exposure in non-smokers, but not in smokers.
  • Additional environmental factors including oral contraceptive use mask the effect of genetics on caffeine metabolism.
  • the role of pharmacogenetics in theacrine pharmacokinetics and pharmacodynamics is of potential importance should CYP1 A2 prove to be an important theacrine elimination pathway.
  • caffeine is related to its ability to antagonize the A1AR, which removes inhibition of the A2A AR leading to NMDA-dependent release of glutamate and dopamine.
  • caffeine's primary effects shift from A1-dependent to A2A-dependent antagonism in tolerant individuals due to A1AR desensitization.
  • Administration of a cocktail containing both A1 and A2A AR antagonists blocks theacrine stimulating activity in rats.
  • simultaneous administration of A1 and A2 A AR antagonists prevents the determination of individual contribution of A1 and A2AAR to the pharmacologic effects of theacrine.
  • Example 3 Improvements in Subjective Feelings, Cognitive Performance, and Hemodynamics
  • the effects of a single dose of theacrine, caffeine, or their combination on subjective feelings, cognitive performance, and hemodynamics in men and women were examined.
  • 24 men and 26 women ingested a placebo theacrine at 25 mg, theacrine at 125 mg, caffeine at 150 mg, or combination of 125 mg theacrine and 150 mg caffeine on five separate occasions, which were separated by approximately one week.
  • Subjects rated their subjective feelings using a 10 cm visual analog scale at 30 minutes, 1, 2, 3, 4, and 5 hours post ingestion and performed the trail making test (TMT) of cognitive performance at baseline and at hours 2 and 4 post ingestion.
  • TTT trail making test
  • the combined theacrine/caffeine treatment resulted in a true synergistic and superior performance in comparison to the pure caffeine, the pure theacrine, or placebo group.
  • the combination of 125 mg theacrine/150 mg caffeine outperformed all other groups, including 275 mg pure caffeine, 275 mg of pure theacrine, and placebo, in measures of cognitive flexibility, attention and task switching, complex-choice reaction time and information processing.
  • the compounds may be administered by any route, including but not limited to oral, sublingual, buccal, ocular, pulmonary, rectal, and parenteral administration, or as an oral or nasal spray (e.g. inhalation of nebulized vapors, droplets, or solid particles).
  • Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intranasal, intravaginal, intravesical (e.g., to the bladder), intradermal, transdermal, topical, or subcutaneous administration.
  • the instillation of theacrine in the body of the patient in a controlled formulation with systemic or local release of the drug to occur at a later time.
  • the drug may be localized in a depot for controlled release to the circulation.
  • compositions of the present invention may be administered in combination with a pharmaceutically acceptable carrier.
  • the active ingredients in such formulations may comprise from 1% by weight to 99% by weight, or alternatively, 0.1% by weight to 99.9% by weight.
  • “Pharmaceutically acceptable carrier” means any carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the user.
  • Useful excipients include microcrystalline cellulose, magnesium stearate, calcium stearate, any acceptable sugar (e.g., mannitol, xylitol), and for cosmetic use an oil-base is preferred.
  • nutraceutical compositions of the present invention may be administered in combination with a nutraceutically acceptable carrier.
  • the active ingredients in such formulations may comprise from 1% by weight to 99% by weight, or alternatively, 0.1% by weight to 99.9% by weight.
  • Nutraceutically acceptable carrier means any carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the user.
  • Useful excipients include microcrystalline cellulose, magnesium stearate, calcium stearate, any acceptable sugar (e.g., mannitol, xylitol), and for cosmetic use an oil-base is preferred.
  • Example 5 Enhanced Coffee Beverage Study
  • VAS Visual analogue scales
  • Vitals including systolic blood pressure, diabolic blood pressure, heart rate, rate pressure product, mean arterial pressure, and pulse pressure were also taken prior to the beverage (A, B, C, D, or E) consumption and at 60, 120, and 180 minutes after as set forth in Table 5.
  • Assessments of VAS Mood, VAS Energy, VAS fatigue, VAS Motivation, VAS Alertness, VAS Focus, VAS Creativity, and VAS Concentration were assessed prior to the beverage (A, B, C, D, or E) consumption and at 60, 120, and 180 minutes after as set forth in Table 6. Comparisons of A, B, and C with D at 180 minutes were calculated as set forth in Table 7.
  • the provided dataset (Table 4) includes baseline screening data for age, body mass (in pounds and kilograms), height (in inches and centimeters), body mass index, systolic blood

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Abstract

Une composition de boisson caféinée améliorée comprend une boisson caféinée combinée à un mélange efficace de méthylliberine et de théacrine améliorant l'humeur, l'énergie, la vigilance, la concentration, la motivation et/ou diminuant la fatigue sans avoir un effet négatif sur la fréquence cardiaque ou la tension artérielle.
PCT/US2020/058138 2019-12-30 2020-10-30 Composition de boisson caféinée améliorée WO2021137926A1 (fr)

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CN202080096737.1A CN115279197A (zh) 2019-12-30 2020-10-30 增强型含咖啡因饮料组合物
BR112022013141A BR112022013141A2 (pt) 2019-12-30 2020-10-30 Composição de bebida cafeinada suplementada com metil-liberina e teacrina; método para preparação de uma bebida cafeinada aprimorada; e composição de bebida de café suplementada com metil-liberina e teacrina
CA3166354A CA3166354A1 (fr) 2019-12-30 2020-10-30 Composition de boisson cafeinee amelioree

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US201962955261P 2019-12-30 2019-12-30
US62/955,261 2019-12-30

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US20150132280A1 (en) * 2013-11-12 2015-05-14 Ortho-Nutra, Llc Theacrine-based supplement and method of use thereof
US20150238494A1 (en) * 2014-02-25 2015-08-27 Jho Intellectual Property Holdings, Llc Highly soluble purine bioactive compounds and compositions thereof
WO2016112475A1 (fr) * 2015-01-13 2016-07-21 陈金锋 Semelle de chaussure perméable à l'air

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150132280A1 (en) * 2013-11-12 2015-05-14 Ortho-Nutra, Llc Theacrine-based supplement and method of use thereof
US20150238494A1 (en) * 2014-02-25 2015-08-27 Jho Intellectual Property Holdings, Llc Highly soluble purine bioactive compounds and compositions thereof
WO2016112475A1 (fr) * 2015-01-13 2016-07-21 陈金锋 Semelle de chaussure perméable à l'air

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DAVIS JEANIE LERCHE: "Antioxidants in Green and Black Tea", WEBMD.COM, 11 September 2008 (2008-09-11), Retrieved from the Internet <URL:https://www.webmd.com/food-recipes/features/antioxidants-in-green-and-black-tea#1> *
ROBERTS, CATHERINE: "Is There More Caffeine in Espresso Than in Coffee?", CONSUMER REPORTS, 13 November 2018 (2018-11-13), XP055838174, Retrieved from the Internet <URL:https://www.consumerreports.org/coffee/is-there-more-caffeine-in-espresso-than-in-coffee/#:-:text=By%20the%20Numbers.mg%20of%20caffeine%20per%20ounce.> *

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CA3166354A1 (fr) 2021-07-08
BR112022013141A2 (pt) 2022-09-06
CN115279197A (zh) 2022-11-01

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