USOO9468645B2

(12) United States Patent (10) Patent No.: US 9.468,645 B2 OWOc (45) Date of Patent: Oct. 18, 2016

(54) HIGHLY SOLUBLE BOACTIVE (2013.01); A61K 9/0019 (2013.01); A61 K COMPOUNDS AND COMPOSITIONS 9/0095 (2013.01); A61K 9/4858 (2013.01); THEREOF A61 K3I/00 (2013.01); A61K 45/06 (2013.01); A23 V 2002/00 (2013.01) (71) Applicant: JHO Intellectual Property Holdings, (58) Field of Classification Search LLC, Davie, FL (US) CPC ...... A23V 2002/00; A23V 2200/31; (72) Inventor: Jack Owoc, Weston, FL (US) A23V 2250/062: A23V 2250/21: A23V 2250/5108: A23V 2250/5118: A23V (*) Notice: Subject to any disclaimer, the term of this 2250/54246; A23V 2250/54252: A23V patent is extended or adjusted under 35 2250/704; A23V 2250/712: A61K 31/522; U.S.C. 154(b) by 3 days. A61K 2300/00; A61K 45/06; A61 K9/00 See application file for complete search history. (21) Appl. No.: 14/628,626 (56) References Cited (22) Filed: Feb. 23, 2015 U.S. PATENT DOCUMENTS (65) Prior Publication Data 837,282 A * 12/1906 Owoc ...... EO1B 9/60 US 2015/O238494 A1 Aug. 27, 2015 238,292 5,973,005 A * 10/1999 D'Amelio, Sr. ... CO7C 277/08 514,565 Related U.S. Application Data 2006/0236421 A1* 10, 2006 Pennell ...... C12N 9/1007 800,278 (60) Provisional application No. 61/944,528, filed on Feb. 2009,0257997 A1* 10, 2009 Owoc ...... A61K9/0014 25, 2014. 424/94.1 (51) Int. C. * cited by examiner A6 IK3I/522 (2006.01) A6 IK 45/06 (2006.01) Primary Examiner – Debbie K Ware A2.3L 2/52 (2006.01) (74) Attorney, Agent, or Firm — David W. Barman A2.3L 2/02 (2006.01) A2.3L I/30 (2006.01) (57) ABSTRACT A6 IK 9/00 (2006.01) The invention provides nutritional Supplements, in powder, A6 IK 9/48 (2006.01) tablet or capsule dosage forms and aqueous formulations, A6 IK3I/00 (2006.01) containing one or more of the purine bioactive compounds (52) U.S. C. described including theacrine and theacrine species. CPC ...... A61 K3I/522 (2013.01); A23L I/30 (2013.01); A23L 2/02 (2013.01); A23L 2/52 20 Claims, No Drawings US 9,468,645 B2 1. 2 HGHLY SOLUBLE PURINE BOACTIVE Theacrine enhances activity levels in a dose-dependent COMPOUNDS AND COMPOSITIONS a. THEREOF Theacrine reduces inflammation. INDEX TO RELATED APPLICATIONS Theacrine reduces pain. Theacrine increases endurance. This application is a non-provisional of, and claims ben Theacrine decreases depression. efit to U.S. Provisional Patent Application Ser. No. 61/944, Theacrine alleviates sleep deprivation. 528 filed Feb. 25, 2014 the disclosure of which is incorpo During sleep deprivation with moderate-intensity exer rated herein by reference in its entirety. 10 cise, theacrine Supplementation may improve perfor TECHNICAL FIELD mance of complex central executive tasks. Theacrine in combination with other psychoStimulants This disclosure of the present invention relates generally has a synergistic effect that enhances the benefits to new chemical entities (NCEs), which are a purine described above. compound structurally related to and abundantly 15 Theacrine may impart a beneficial hypoglycemic effect in present in Camelia kuchu, Camelia sinensis and several the management of hyperglycemia. Coffea species. The disclosure relates more specifically to 1.3.7.9-tetramethyluric acid (theacrine), (O(2), 2-Methoxy The synthesis of theacrine is achieved as follows: 1,9-dimethyl-7H-purine-6,8-dione (liberine) and (O(2), 1.7, Theacrine is synthesized from by one step. At the 9-trimethyluric acid (methylliberine) wherein a basic uric presence of potassium carbonate, uric acid is methylated by acid structure has been partially or fully methylated in 2, 3 trimethyl phosphate to give theacrine. or 4 positions. This disclosure relates specifically to The one step pathway is depicted below: theacrine, and theacrine species Such as liberine, and meth ylliberine and compositions thereof. The disclosure of the present invention includes synthetic O procedures of 1.3.7.9-tetramethyluric acid, O(2), 1.9-trim 25 ethyluric acid and O(2), 1.7.9-trimethyluric acid and their Subsequent purification to yield compounds which are HN ) O K2CO3, trimethylphosphate 99.9% pure and melting points of 228.9° C., 220° C. and 1. N --Reflux 215° C. respectively. O N 30 H H The disclosure of the present invention further relates to O compositions of matter wherein one or more of the purine alkaloid compounds is administered to mammals in combi nation with other psychoStimulants including, but not lim ited to caffeine, , , yohimbine, combinations thereof, and other compounds known in the art 35 to impart a psychoStimulant effect. In addition this disclosure of the present invention relates to nutritional Supplements, in powder, tablet or capsule dosage forms, aqueous formulations, containing one or more Stable aqueous compositions of matter useful for oral of the purine bioactive compounds described. 40 administration of at least one biologically-active form of a In addition this disclosure of the present invention relates purine alkaloid compound structurally related to caffeine to to nutritional Supplements, in powder, tablet or capsule a mammalian Subject, which compositions comprise: dosage forms, as solutions or Suspensions, aqueous formu a) 1,3,7,9-tetramethyluric acid (theacrine), (O(2), 1.9- lations, which may be used as stimulant of the central trimethyluric acid (ibertine) and (O(2), 1.7.9-trimethy nervous system and metabolic stimulant. It may also be used 45 luric acid (methylliberine) wherein a basic uric acid medically to increase locomotor activity, increase, maintain structure has been partially or fully methylated in 2, 3 and extend locomotor activity, enhance activity levels in a or 4 positions dose-dependent manner, reduce inflammation, reduce pain, increase endurance, reduce depression, impart a beneficial b) Water; hypoglycemic effect and alleviate sleep deprivation. 50 c) Water (pH range of 2.0-8.5); and d) Acqueous buffer solutions (pH range: 1.5-9.0). BACKGROUND In one embodiment, the present invention provides stable aqueous compositions of matter useful for oral administra Many stimulant nutritional Supplements are available at tion of at least one biologically-active form of a purine various retail outlets, in many dosage forms, including 55 alkaloid compound structurally related to caffeine to a tablets, capsules, powders, and liquids intended for human mammalian Subject, which compositions comprise: consumption. Most of them feature caffeine as the main a) 1,3,7,9-tetramethyluric acid (theacrine), (O(2), stimulant. Theacrine offers the advantages of caffeine with 2-Methoxy-1,9-dimethyl-7H-purine-6,8-dione (liber the addition of the other benefits included in the summary ine) and (O(2), 1.7.9-trimethyluric acid (methylliber below: 60 ine) wherein a basic uric acid structure has been SUMMARY OF THE INVENTION partially or fully methylated in 2, 3 or 4 positions b) Aqueous buffered solutions (pH range: 1.5-9.0). Some of the benefits of the present invention include: In one embodiment, the composition provides said Theacrine increases locomotor activity. 65 theacrine, or the theacrine species (as used, theacrine species Theacrine) increases locomotor activity and maintains it includes liberine and methylliberine) are present in said for extended time. aqueous composition in any amount between about 0.01% US 9,468,645 B2 3 4 and about 10% by weight based on the total weight of said prising the steps of preparing a composition according to composition, including all percentages and ranges of per the present invention; and orally administering the compo centages therebetween. sition to said mammalian Subject. In one embodiment, the composition of the present inven tion is further comprising one or more nutritional adjuvant The present invention also contemplates a method for materials selected from the group consisting of flavoring increasing endurance in a mammalian Subject, said method agents, colorants, viscosity modifiers, preservatives, fra comprising the steps of preparing a composition according grances, amino acids and their salts, vitamins, minerals, to the present invention; and orally administering the com essential fatty acids, , co-enzymes, mono-glycer position to said mammalian Subject. ides, di-glycerides, tri-glyceride ester oils emulsifiers, 10 The present invention also contemplates a method for hydrolyzed proteins, whey protein, stabilizers, flow modi reducing depression in a mammalian Subject, said method fiers, viscosity improvers, chelating agents, anti-oxidants, comprising the steps of preparing a composition according anti-microbials, benzoates, alcohols, esters of para-hydroxy to the present invention; and orally administering the com benzoic acid, propionates, preservatives, Surfactants (includ position to said mammalian Subject. ing anionic, cationic or nonionic Surfactants) or combina 15 tions thereof. The present invention also contemplates a method for In one embodiment, the composition of the present inven alleviating the deleterious effects of hypergycemia in a tion the total amount of said one or more nutritional adjuvant mammalian Subject, said method comprising the steps of materials present is present in any amount between about preparing a composition according to the present invention; 0.01% and about 10% by weight based on the total weight and orally administering the composition to said mammalian of said composition. Subject. In one embodiment, the composition of the present inven The present invention also contemplates a method for tion is further comprising one or more natural beverages, alleviating the deleterious effects of sleep deprivation in a including without limitation, milk products, soy products, mammalian Subject, said method comprising the steps of ice cream, yoghurt, citrus fruit juices, non-citrus fruit juices, 25 preparing a composition according to the present invention; and vegetable juices, or components of any of the foregoing. and orally administering the composition to said mammalian In one embodiment, the composition of the present inven Subject. tion has said one or more natural beverages is present in any amount between about 0.1% and about 99% by weight based The present invention also contemplates a method in a on the total weight of said composition. 30 mammalian Subject, said method comprising the steps of In one embodiment, the composition of the present inven preparing a composition according to the present invention; tion is comprising an anti-microbial preservative present in and orally administering the composition to said mammalian an effective amount to inhibit microbial growth. Subject wherein the administering is of one or more of purine In one embodiment, the composition of the present inven described herein in combination with other psy tion comprises a preservative selected from the group con 35 chostimulants in any possible proportion in order to further sisting of one or more esters of para-hydroxybenzoic acid, enhance the benefits according to the methods of the present propionates, one or more Sorbate salts, or combinations invention. thereof. As contemplated herein, the method steps of orally The present invention also contemplates a method for administering, in one embodiment, further comprises the administering a bioactive form of theacrine to a mammalian 40 Subject, said method comprising the steps of preparing a chronic administration of a composition according to a composition according to the present invention; and orally mammalian Subject. administering the composition to said mammalian Subject. As contemplated herein, the method steps of orally The present invention also contemplates a method for administering, in one embodiment, further comprises the increasing locomotor activity in a mammalian Subject, said 45 acute administration of a composition according to a mam method comprising the steps of preparing a composition malian Subject. according to the present invention; and orally administering the composition to said mammalian Subject. The Table 1 below is data indicating assay results for The present invention also contemplates a method for stability of a theacrine Solution prepared at 1.3 mg/ml and increasing locomotor activity and maintaining for extended 50 stored in USP Type I Glass vials for 15 weeks at RT and time this activity in a mammalian Subject, said method 40° C. comprising the steps of preparing a composition according to the present invention; and orally administering the com TABLE 1. position to said mammalian Subject. Theacrine Stability Data The present invention also contemplates a method for 55 enhanced activity levels in a dose-dependent manner in a Initial 1-wk 2-wk 4-wk 8-wk 15-wk mammalian Subject, said method comprising the steps of Storage: Room preparing a composition according to the present invention; Temperature (RT) and orally administering the composition to said mammalian Subject. 60 Assay 99.6 98.7 1OO1 99.2 99.9 99.3 The present invention also contemplates a method for Storage: 40 C. reducing inflammation in a mammalian Subject, said method Assay 99.6 98.2 98.9 98.7 98.6 98.0 comprising the steps of preparing a composition according to the present invention; and orally administering the com position to said mammalian Subject. 65 Table 2 below shows data indicating assay values of The present invention also contemplates a method for theacrine solutions at 0.1%, 0.2% and 0.4% stored in USP reducing pain of a mammalian Subject, said method com type I glass vials for 3 months at 40°C. US 9,468,645 B2 5 6 TABLE 2 solution provided hereby may be any amount between about 0.1% and about 20% by weight based on the total weight of Theacrine Stability Data the aqueous Solution, including all percentages and ranges of percentages therebetween. According to another embodi Storage: 40 C. Initial 10-d 1-M 2-M 3-M ment, the total concentration of theacrine species in an 0.1% Solution 100.6 100.4 101 100.4 100.7 aqueous Solution provided hereby may be any amount 0.2% Solution 99.8 98.6 98.9 97.5 99.4 between about 0.1% and about 25% by weight based on the 0.4% Solution 94.1 92.3 94.9 95.3 95.8 total weight of the aqueous Solution, including all percent ages and ranges of percentages therebetween. According to 10 another embodiment, the total concentration of Theacrine DETAILED DESCRIPTION OF THE species in an aqueous Solution provided hereby may be any PREFERRED EMBODIMENTS amount between about 0.1% and about 30% by weight based on the total weight of the aqueous Solution, including all The present invention provides aqueous compositions of percentages and ranges of percentages therebetween. In an matter Suitable for oral administration to mammalian Sub 15 alternate embodiment, theacrine (or any one or more jects, including without limitation humans, which compo theacrine species) may be added to a natural beverage in any sitions comprise theacrine species in Solid or in liquid amount provided that an aqueous solution or Suspension vehicles (carriers) that have been synthesized in commercial results. quantities by Vital Pharmaceuticals, Inc., d/b/a VPX/Redline In addition, a composition according to the present inven tion also includes nutritional adjuvant materials including of Davie, Fla.; theacrine itself has the general structure: flavoring agents, colorants, viscosity modifiers, preserva tives, chelating agents, antioxidants, Surface modifiers and Structure I other nutritional adjuvant materials. Other nutritional adju vant materials include any Substance which is generally 25 recognized as promoting the health or function of a mam O N N malian organism, including humans, or benefiting a compo sition useful thereof in terms of its efficacy, appearance, N X=o stability, consistency, aroma, or viscosity. Such substances 1. V include, but are not limited to, other amino acids and their O 30 salts, vitamins, minerals, essential fatty acids, enzymes, mono-glycerides, di-glycerides, tri-glyceride ester oils (in cluding, for example vegetable oils and animal fats) emul sifiers, hydrolyzed proteins, whey protein, stabilizers, flow Properties modifiers, Viscosity improvers, chelating agents, enzymes, 35 Surfactants, whether anionic, cationic or nonionic, and com Molecular formula CoH2N4O3 binations thereof. The total amount of the one or more Chemical name 1,3,7,9-Tetramethyluric acid Molar mass 224.21 g/mol nutritional adjuvant materials above present in a composi CAS Registry Number 2309-49-1 tion according to this disclosure is present in any amount between about 0.01% and about 50% by weight based on the 40 total weight of said composition, including all percentages The material described by Structure I above, and the and ranges of percentages therebetween. corresponding text in the description, including any and all In addition to ingredients containing adjuvant materials, a of their derivative chemical forms, are all theacrine species composition according to one embodiment of the present and are, as Such, the Subject of the present disclosure. invention also comprises one or more natural beverages. A Aqueous compositions of matter Suitable for oral admin 45 natural beverage, as used herein, is a beverage Suitable for istration to mammalian Subjects according to this disclosure human or animal consumption which contains the pulp. may be caused to have any pH in the range of between about juice or any other constituent of a naturally-occurring fruit, 1.5 and about 8.5 as desired, by adjusting Such compositions vegetable, or animal product whether from the wild, cul using additions of appropriate amounts of strong or weak tured, cultivated on a farm or otherwise domesticated by acids or bases including without limitation aqueous mineral 50 Man. Natural beverages include without limitation materials acids including HCl, H3PO4, and bases including sodium including, but not limited to as milk products, soy products, hydroxide, ethanolamines, etc. ice cream, yoghurt, citrus fruit juices, non-citrus fruit juices, To prepare a composition according to one embodiment and vegetable juices, or components of any of the foregoing, of the present invention, one may simply add a desired wherein said natural beverages are present in any effective amount of theacrine to a selected Volume of water, and 55 amount to impart flavor to the compositions, which are any sufficient stirring is affected to cause dissolution of the amount between about 0.1% and about 99% by weight based theacrine to afford an aqueous composition. Furthermore, on the total weight of said composition, including all per according to one embodiment, the solution may be buffered centages and ranges of percentages there between. before the addition of theacrine or the solution may be may In addition to ingredients containing adjuvant materials, a be made more acidic or alkaline prior to the addition of 60 composition according to one embodiment of the present theacrine. According to another embodiment, the total con invention comprises one or more synthetic beverages. A centration of theacrine species in an aqueous solution pro synthetic beverage is any beverage that is not a natural vided hereby may be any amount between about 0.01% and beverage. about 20% (or more) by weight based on the total weight of In general, a composition according to one embodiment the aqueous Solution, including all percentages and ranges of 65 of the present invention is provided by combining and percentages therebetween. According to another embodi mixing the ingredients selected, including theacrine and any ment, the total concentration of theacrine in an aqueous desired quantity of any one or more other ingredients US 9,468,645 B2 7 8 specified herein. One advantage of compositions according electrolytes, amino trace elements, colorings, flavors, arti to this disclosure is that they may be packaged at pH levels ficial Sweeteners, and anti-oxidants. as low as about pH 2, in the cold or at about room 3. An oral Solid composition in the form of a capsule temperature (alternative embodiment) or only slightly (LiCap(R) with a liquid composition as fill material, said elevated temperature (alternative embodiment), as opposed 5 liquid fill material being substantially stable at room tem to many prior art compositions which typically require hot perature for normal warehouse storage conditions, stable at packaging methods that utilize specialized and expensive 104°F (40 C. degrees) for shipping in hot weather trucks equipment and packaging materials. and/or overseas containers, and stable at 39° F (4 C. Thus, it is evident that a composition according to one degrees) in coolers so that it can be stored under refrigera 10 tion conditions. The composition comprising a Suitable embodiment of the present invention is made quite palatable lipophilic solvent or vehicle, a physical stabilizing ingredi by a mammalian Subject, including human Subjects desiring ent, one or more surfactants, and one or more buffer salts to administer theacrine orally in an aqueous mixture. Typical that can render the composition pH stable. The composition serving sizes may be any serving size in the range of about in one embodiment, contains psychoStimulants, , 1 milligram to about 50 grams, in an aqueous Solution that 15 oligonucleotides, the monophosphates, diphosphates, is from about 20 ml to about 2500 ml in volume. The triphosphates and cyclic derivatives of these nucleotides, composition of theacrine in an aqueous composition accord and amino acids, vitamins and vitamin-like isoprenoids, ing to this disclosure is limited only by the solubility limit peptides and one or more additional components selected of the theacrine and which may exceed 50 grams per liter from the group consisting of lipids, medium and short chain and concentrations at or near the Solubility limit are herein triglycerides, starches, polyols, carbohydrates, minerals, provided by contacting excess amounts of the theacrine in electrolytes, amino trace elements, colorings, and anti-oxi contact with water or an aqueous solution to provide a dants. solution saturated with theacrine. Such saturated solutions 4. An oral liquid composition containing from 1 gram to may then be diluted slightly, to afford a concentrate from 100 grams of protein and from 1 g ram to 100 g of which other theacrine containing compositions may be con 25 carbohydrates per serving comprising Theacrine, said liquid veniently provided. being Substantially stable at room temperature for normal Descriptions of Compositions warehouse storage conditions, stable at 104° F (40 C. The following compositions are illustrative and not meant degrees) for shipping in hot weather trucks and/or overseas to limit the scope of the present invention. containers, and stable at 39°F. (4 C. degrees) in coolers so 1. An oral liquid composition (Ready-to-Drink) compris 30 that it can be stored under refrigeration conditions. The ing Theacrine, said composition with a pH of about 2 to 8.5 composition comprising an acid stable protein isolates, or a being substantially stable at room temperature for normal combination or blend of protein isolates, concentrates and warehouse storage conditions, stable at 104° F (40 C. hydrolyzates and caseins in micellar forms, a Suitable aque degrees) for shipping in hot weather trucks and/or overseas ous solvent or vehicle, a non-aqueous vehicle, a preserva containers, and stable at 39° F (4 C. degrees) in coolers so 35 tive, a physical stabilizing ingredient, one or more surfac that it can be stored under refrigeration conditions. The tants, and one or more buffer salts that can render the composition comprising a suitable aqueous solvent or composition pH stable. The composition, in one embodi vehicle, a non-aqueous vehicle, a preservative, a physical ment, contains psychostimulants, nucleotides, oligonucle stabilizing ingredient, one or more surfactants, and one or otides, the monophosphates, diphosphates, triphosphates more buffer salts that can render the composition pH stable. 40 and cyclic derivatives of these nucleotides, and amino acids, The composition, in one embodiment contains psychoStimu Vitamins and vitamin-like isoprenoids, peptides and one or lants, nucleotides, oligonucleotides, the monophosphates, more additional components selected from the group con diphosphates, triphosphates and cyclic derivatives of these sisting of lipids, starches, carbohydrates, polyols, minerals, nucleotides, and amino acids, vitamins and vitamin-like electrolytes, amino trace elements, colorings, flavors, arti isoprenoids, peptides and one or more additional compo 45 ficial Sweeteners, and anti-oxidants. nents selected from the group consisting of lipids, starches, 5. An aqueous injectable composition for human con carbohydrates, polyols, minerals, electrolytes, amino trace Sumption said composition being isotonic and sterile in elements, colorings, flavors, artificial Sweeteners, and anti nature comprising Theacrine, said injectable preparation oxidants. with a pH of about 2, being substantially stable at room 2. An oral liquid composition for buccal Sublingual 50 temperature for normal warehouse storage conditions, stable administration comprising Theacrine, said composition with at 104°F (40 C. degrees) for shipping in hot weather trucks a pH of about 2 to 8.5 being substantially stable at room and/or overseas containers, and stable at 39° F (4 C. temperature for normal warehouse storage conditions, stable degrees) in coolers so that it can be stored under refrigera at 104°F (40 C. degrees) for shipping in hot weather trucks tion conditions. The composition comprising a Suitable and/or overseas containers, and stable at 39° F (4 C. 55 aqueous solvent, a preservative, a physical stabilizing ingre degrees) in coolers so that it can be stored under refrigera dient and one or more buffer salts that can render the tion conditions. The composition comprising a Suitable composition pH stable. The composition, in one embodi aqueous solvent or vehicle, a non-aqueous vehicle, a pre ment, contains psychostimulants, nucleotides, oligonucle servative, a physical stabilizing ingredient, one or more otides, the monophosphates, diphosphates, triphosphates Surfactants, and one or more buffer salts that can render the 60 and cyclic derivatives of these nucleotides, and amino acids, composition pH stable. The composition, in one embodi peptides, proteins and carbohydrates. ment, contains psychostimulants, nucleotides, oligonucle 6. An emulsion injectable composition for human con otides, the monophosphates, diphosphates, triphosphates Sumption said composition being isotonic and sterile in and cyclic derivatives of these nucleotides, and amino acids, nature comprising Theacrine, said injectable preparation Vitamins and vitamin-like isoprenoids, peptides and one or 65 with a pH of about 2, being substantially stable at room more additional components selected from the group con temperature for normal warehouse storage conditions, stable sisting of lipids, starches, carbohydrates, polyols, minerals, at 104°F (40 C. degrees) for shipping in hot weather trucks US 9,468,645 B2 10 and/or overseas containers, and stable at 39°F (4C. degrees Example III in coolers so that it can be stored under refrigeration conditions. The composition comprising a suitable aqueous Solvent, pharmaceutically acceptable oil (sesame, olive, castor, peanut, cotton seed, etc.), a natural emulsifier Such as INGREDIENTS % Wiw lecithin or any other synthetic emulsifier, be it of the Theacrine 2.10 polysorbate or ethoxylated glyceride type, a preservative, a Caffeine 4.2O Peptides 3.00 physical stabilizing ingredient and one or more buffer salts AMP 12.SO that can render the composition pH stable. The composition, UTP O.10 10 in one embodiment, contains psychoStimulants, nucleotides, Ubiquinone 3.20 oligonucleotides, the monophosphates, diphosphates, Propylene Glycol 2O.O USP 40.0 triphosphates and cyclic derivatives of these nucleotides, Polysorbate 80 S.O and amino acids, peptides, proteins and carbohydrates. Benzyl alcohol 1.00 Buffer Salt(s) QS to adjust pH 15 Purified Water QS to 100 EXAMPLES

Ready to Drink Formulation Fill Material Composition for Capsule

Example I Example I

25 INGREDIENTS (Ready-to-Drink Formulation) % Wiw INGREDIENTS % Wiw Purified water 97.1 Theacrine 2.10 Theacrine 1.00 Medium chain triglyceride 1S.O Caffeine 2.00 Peptides 3.00 Gamma Butyrobetaine O.O156 30 AMP 12.SO Glycerin 1.067 UTP O.10 Anserine O.OS2 Ubiquinone 3.30 Caffeine O.O6 Oleic Acid 52.O Tanshinoate O.OOOOOO9 Purified Water 1.0-10.O L-Leucine O. 104 L-Isoleucine O.OS2 35 L-Valine O.O2O8 1,3-di-n-propyl-7-propargylxanthine 1E-10 Example II Geranamine O.OOO4 Citric acid to pH 3.33 O.179 Sodium benzoate O.OS2 40 Potassium Sorbate O.O1 INGREDIENTS % ww Bis picolinate vanadium O.OOOOOO2 Salt O.OOS Theacrine 2.10 Potassium phosphate dibasic O.O2O6 Peptides 3.00 Sodium Erythorbate O.OOOOO1 AMP 12.SO Nisaplin O.OOOOO1 45 UTP O.10 Ubiquinone 3.30 Sucralose O.O73 Polysorbate 80 2SO Malic acid O.083 PEG-40 Hydrogenated Castor Oil 38.00 Flavor Melon O. 105 PEG esters and monoglycerides 1S.O Purified Water QS to 100 50 Example II Example III

55 INGREDIENTS % Wiw INGREDIENTS % Wiw Theacrine 2.10 Caffeine 4.20 Theacrine 2.10 Peptides 3.00 Peptides 3.00 AMP 12.SO AMP 12.SO UTP O.10 60 UTP O.10 Ubiquinone 3.2O Ubiquinone 3.30 Ethoxydiglycol 2O.O PEG-400 4S.O Alcohol USP SO.O PEG esters and monoglycerides 9.OO Benzyl alcohol 1.OO Polysorbate 80 2O.O Buffer Salt(s) QS to adjust pH Buffer Salt(s) QS to adjust pH Purified Water QS to 100 65 Purified Water QS to 100 US 9,468,645 B2 12 Medium Range pH RTD Protein Blend Formulations Aqueous Injectable Formulations Example I Ingredient % wiw Per 16 oz Serving Theacrine 1.OO 2.10 Whey Protein Isolate 6.OOO 3O.OO Whey Protein Concentrate O.640 3.20 Ingredient % wiv Whey Hydrolysate O.32O 1.60 Micellar casein O.32O 1.60 Theacrine 6.25 O.OOO O.OO Caffeine 12.5 Casein Protein Hydrolysate AMP 12.5 Potassium Chloride O.O76 O.38 10 UTP O.10 Ascorbic Acid O.O12 O.O6 Amino Acids 3.0-7.0 Vitamin E TPGS O.OS2 O.26 Polysorbate 80 O40 Riboflavin 100 O.OOO OOOOOOO10 Sodium CMC OSO Niacin O.OOO O.OO20 Sodium Chloride O.90 Pyrodoxine HCI O.OOO OOOOOO7 15 Benzyl alcohol O.90 Panthothenate O.OOO O.OO11 Buffer Salt(s) QS to adjust to pH 3-6.5 Magnesium Maleate O.O20 O.1OOO Sodium Hydroxide QS to adjust to pH 3-6.5 d- O.O40 O.2OOO Water for Injection QS to 100 Centromix E O600 3.00 Saflower Oil 1.200 6.OO Sunflower Oil 1.200 6.OO Medium Chain Triglycerides O.800 4.OO Example II L-Glutamine O.O2S O.13 Glucose Polymers (Rice trin) O.800 4.OO Waxy Maize Starch 1.OOO S.OO O.100 OSO High Amylose Starch (Amylose ADP11P) Ingredient % wiv Magnesium Citrate O.124 O.62 25 Microcrystalline Cellulose O.100 OSO Theacrine 6.25 Malic Acid O.140 O.70 Caffeine 12.SO Citric acid to pH 6.5 O.S66 2.83 UTP O.10 Sodium Citrate to pH 6.5 O.140 O.70 Amino Acids 3.0-7.0 Sucralose O.O11 O.O6 Polysorbate 80 O40 Glycerin 3.OOO 1S.OO 30 Sorbitol 40.00 Na2EDTA O.OSO O.25 Sodium Chloride O.90 Sodium Benzoate O.O90 O45 Benzyl alcohol O.90 Potassium Sorbate O.190 O.9S Buffer Sat(s) QS to adjust to pH 3-6.5 Water Sodium Hydroxide QS to adjust to pH 3-6.5 Water for Injection QS to 100 35 Low pH RTD Protein Formulations Example III

Per 16 oz serving % Wiw 40 Theacrine 2.10 O.25 Whey Protein Isolate Acid Stable 44.44 9.26 Ingredient % wiv Sucralose O.12 O.O2S Sodium EDTA O.24 O.OSO Theacrine 6.25 12.5 Potassium Sorbate O.96 O.200 Caffen Sodium Benzoate O48 O.100 Polysorbate 80 O40 Citric Acid to pH 3.0 QS QS 45 AMP 12.SO Malic Acid to pH 3.0 QS QS UTP O.10 Water 433.8 90.37 Amino Acids 3.0-7.0 Sodium Citrate OSO 480 Sodium Chloride O.90 Benzyl alcohol O.90 Buffer Salt(s) QS to adjust to pH 3-6.5 50 Sodium Hydroxide QS to adjust to pH 3-6.5 Low pH RTD Protein Formulations Water for Injection QS to 100

Per 16 oz serving % Wiw 55 Emulsion Injectable Formulations Theacrine 2.10 O.25 Whey Protein Isolate Acid Stable 44.44 9.26 Example I Sucralose O.12 O.O2S Waxy Maize Starch 4.80 1.00 Glucose Polymers (Rice trin) O.96 O.20 Nal EDTA O.24 O.OSO 60 Potassium Sorbate O.96 O.200 Ingredient % wiv Sodium Benzoate O48 O.100 Citric Acid to pH 3.0 QS QS Theacrine 6.25 Malic Acid to pH 3.0 QS QS Caffeine 12.5 Water QS QS AMP 12.5 UTP O.10 TOTAL 480 65 Amino Acids 3.0-7.0 Sesame Oil 2.0-12.O US 9,468,645 B2 14 -continued modified. This also includes combination of the features and/or limitations of one or more of the independent claims Ingredient % Wiw with features and/or limitations of another independent Polysorbate 80 O.40 claim to arrive at a modified independent claim, with the Sodium Chloride O.90 remaining dependent claims in their original text being read Benzyl alcohol O.90 and applied to any independent claim so modified. Accord Buffer Salt(s) QS to adjust to pH 3-6.5 ingly, the present disclosure is intended to cover all Such Sodium Hydroxide QS to adjust to pH 3-6.5 modifications and alterations and is not intended to be Water for Injection QS to 100 necessarily limited by any one or more particular strict 10 interpretations of the claims that now follow. What is claimed is: Example II 1. Stable aqueous compositions for oral administration of at least one biologically-active form of a purine alkaloid compound structurally related to caffeine to a mammalian 15 Subject, which compositions comprise: Ingredient % Wiw a) 1,3,7,9-tetramethyluric acid (theacrine), (O(2), Theacrine 6.25 2-Methoxy-1,9-dimethyl-7H-purine-6,8-dione (liber Caffeine 12.5 ine) and (O(2), 1.7.9-trimethyluric acid (methylliber AMP 12.SO ine), said liberine and methylliberine collectively UTP O.10 Amino Acids 3.0-7.0 referred to as theacrine species, wherein a basic uric Olive Oil 1.0-15.O acid structure has been partially or fully methylated in Lecithin OSO-5.0 2, 3 or 4 positions; and Sorbitol 3O.OO b) at least one aqueous buffered solution having a pH Sodium Chloride O.90 Benzyl alcohol O.90 range of about 1.5-9.0. Buffer Sat(s) QS to adjust to pH 3-6.5 25 2. A composition according to claim 1 wherein said Sodium Hydroxide QS to adjust to pH 3-6.5 theacrine, or theacrine species are present in said aqueous Water for Injection QS to 100 composition in any amount between about 0.01% and about 10% by weight based on the total weight of said composi tion, including all percentages and ranges of percentages Example III 30 therebetween. 3. A composition according to claim 1, further comprising one or more nutritional adjuvant materials selected from the group consisting of flavoring agents, colorants, viscosity Ingredient % Wiw modifiers, preservatives, fragrances, amino acids and their 35 salts, vitamins, minerals, essential fatty acids, enzymes, Theacrine 6.25 co-enzymes, mono-glycerides, di-glycerides, tri-glyceride Caffeine 12.5 Peanut Oil 1.0-15.O ester oils emulsifiers, hydrolyzed proteins, whey protein, Polysorbate 80 O.2-1O.O stabilizers, flow modifiers, viscosity improvers, chelating AMP 12.SO agents, anti-oxidants, anti-microbials, benzoates, alcohols, UTP O.10 40 Amino Acids 3.0-7.0 esters of para-hydroxybenzoic acid, propionates, preserva Sodium Citrate OSO tives, Surfactants, including anionic, cationic or nonionic Sodium Chloride O.90 Surfactants, or combinations thereof. Benzyl alcohol O.90 4. A composition according to claim 3 wherein the total Buffer Salt(s) QS to adjust to pH 3-6.5 Sodium Hydroxide QS to adjust to pH 3-6.5 amount of said one or more nutritional adjuvant materials Water for Injection 45 present is present in any amount between about 0.01% and QS to 100 about 10% by weight based on the total weight of said composition. A composition as provided herein may be administered 5. A composition according to claim 1 further comprising chronically. As used herein, "chronically has its normal one or more natural beverages, including, milk products, soy meaning, which generally means repeated ingestion over a 50 products, ice cream, yoghurt, citrus fruit juices, non-citrus period of several days, several weeks or even several fruit juices, vegetable juices, components of any of the months. "Chronic' is generally not acute. foregoing, or combinations thereof. Consideration must be given to the fact that although this 6. A composition according to claim 5 wherein said one disclosure has been described and disclosed in relation to or more natural beverages is present in any amount between certain preferred embodiments, obvious equivalent modifi 55 about 0.1% and about 99% by weight based on the total cations and alterations thereof will become apparent to one weight of said composition. of ordinary skill in this art upon reading and understanding 7. A composition according to claim 1, comprising an this specification and the claims appended hereto. This anti-microbial preservative present in an effective amount to includes Subject matter defined by any combination of any inhibit microbial growth. one of the various claims appended hereto with any one or 60 8. A composition according to claim 7 wherein said more of the remaining claims, including the incorporation of preservative comprises a preservative selected from the the features and/or limitations of any dependent claim, group consisting of one or more esters of para-hydroxy singly or in combination with features and/or limitations of benzoic acid, propionates, and one or more Sorbate salts. any one or more of the other dependent claims, with features 9. A method for administering a bioactive form of and/or limitations of any one or more of the independent 65 theacrine to a mammalian Subject said method comprising claims, with the remaining dependent claims in their original the steps of preparing a composition according to claim 1: text being read and applied to any independent claims so and orally administering said composition. US 9,468,645 B2 15 16 10. The method of claim 9 wherein said method further comprises increasing locomotor activity in the mammalian Subject. 11. The method of claim 10, wherein said increasing locomotor activity is maintained for extended time by chronic oral administration of said composition to the mam malian Subject. 12. The method of claim 9 further comprising providing enhanced activity levels in a dose-dependent manner in the mammalian Subject. 10 13. The method of claim 9 further comprising reducing inflammation in the mammalian Subject. 14. The method of claim 9 further comprising reducing pain of the mammalian Subject. 15. The method of claim 9 further comprising increasing 15 endurance in the mammalian Subject. 16. The method of claim 9 further comprising reducing depression in the mammalian Subject. 17. The method of claim 9 further comprising alleviating the deleterious effects of hypergycemia in the mammalian Subject. 18. The method of claim 9 further comprising alleviating the deleterious effects of sleep deprivation in the mammalian Subject. 19. The method of claim 9 further comprising adminis 25 tering one or more of purine alkaloids in combination with at least one psychoStimulant. 20. The method of claim 9, wherein said step of orally administering comprises chronic or acute administration of a composition to the mammalian Subject. 30 k k k k k