Quick viewing(Text Mode)

(12) United States Patent (10) Patent No.: US 8,466,187 B2 Kramer Et Al

(12) United States Patent (10) Patent No.: US 8,466,187 B2 Kramer Et Al

USOO8466 187B2

(12) United States Patent (10) Patent No.: US 8,466,187 B2 Kramer et al. (45) Date of Patent: *Jun. 18, 2013

(54) AMINO COMPOSITIONS OTHER PUBLICATIONS (75) Inventors: Ronald Kramer, Phoenix, AZ (US); Ramaswamy et al., J. Raman Spectrosc. 34:50-56 (2003). Alexander Nikolaidis, New Kallikratia Rajkumar and Ramakrishnan, J. Raman Spectrosc. 31:1107-1112 (2000). (GR) Petrosyan et at, J. Molecular Structure 794:160-167 (2006). Jablecka et al., MedSci Monit 10(I):CR29-32 (2004). (73) Assignee: Thermolife International, LLC, Maynard et al., J. Nutr. 131:287-290 (2001). Phoenix, AZ (US) Rytlewski et al., European Journal of Obstetrics & Gynecology and Reproductive Biology 138:23-28 (2008). (*) Notice: Subject to any disclaimer, the term of this Schwedheirn et al., Br J Clin Pharmacol 65(1):51-59 (2007). patent is extended or adjusted under 35 Smith et al., J. Thorac Cardiovasc. Surg 132:58-65 (2006). U.S.C. 154(b) by 6 days. Rytlewski et al., Eur J. Clin Invest 35 (1):32-37 (2005). This patent is Subject to a terminal dis Ming et al., Circulation 110:3708-3714 (2004). claimer. Romero et al., Cardiovascular Drug Reviews 24(3-4):275-290 (2006). Oka et al., Vasc Med 10:265-274 (2005). (21) Appl. No.: 13/038,615 Hayashi et al., PNAS 102(38): 13681-13686 (2005). Grasemann et al., Eur Respir J 25:62-68 (2005). (22) Filed: Mar. 2, 2011 Boger, J. Nutr 137:1650S-1655S (2007). Beghetti et al., J. Thorac Cardiovasc. Surg 132(6): 1501-1502 (2006). (65) Prior Publication Data Larsen et al., B. Acta Physiol 191(1):59-66 (2007). US 2011 FO313043 A1 Dec. 22, 2011 Berge, Journal of Pharmaceutical Sciences, Jan. 1977, vol. 66, No. 1. Takahashi et al., “Characterization of the influence of donors on intestinal absorption of macromolecules.” International Related U.S. Application Data Journal of Pharmaceutics vol. 286:89-97 (2004). Fetih et al., "Nitric oxide donors can enhance the intestinal transport (63) Continuation-in-part of application No. 12/336,938, and absorption of insulin and Asu 1.7-eel in rats.” Journal filed on Dec. 17, 2008, now Pat. No. 8,034,836, which of Controlled Release vol. 106:287-297 (2005). is a continuation of application No. 11/950,273, filed Fetih et al., “Excellent Absorption Enhancing Characteristics of NO on Dec. 4, 2007, now Pat. No. 7,777,074. Donors for Improving the Intestinal Absorption of Poorly Absorbable Compound Compared with Conventional Absorption Enhancers.” (60) Provisional application No. 60/973.229, filed on Sep. Drug Metab. Pharmacokinet, vol. 21(3):222-229 (2006). 18, 2007. Aniya et al., “Evaluation of Nitric Oxide Formation from Nitrates in Pig Coronary Arteries,” Jpn. J. Pharmacal. vol. 71: 101-107 (1996). (51) Int. Cl. T.F. Luscher, "Endogenous and exogenous nitrates and their role in A6 IK3 L/45 (2006.01) myocardial ischaemia.” Br. J. Clin. Pharmacol. vol. 34:29S-35S (1992). (52) U.S. Cl. Shiraki et al., “The hypotensive mechanisms of the new anti-anginal USPC ...... 514/400 drug, N-(2-Hydroxyethyl) Nicotinamide Nitrate (SG-75) in beagle (58) Field of Classification Search dogs.” Japan. J. Pharmacol. vol. 31:921-929 (1981). USPC ...... 5147400 CFIndustries, “Material Safety Data Sheet for Ammonium See application file for complete search history. Nitrate Solution (UAN).” available at www.cfindustries.com/pdf UANMSDS.pdf Oct. 25, 2006. (56) References Cited Slart et al., “Nitrate Administration Increases Blood Flow in Dys functional but Viable Myocardium, Leading to Improved Assessment U.S. PATENT DOCUMENTS of Myocardial Viability: A PET Study,” J. Nucl. Med... vol. 47: 1307 3,886,040 A 5, 1975 Chibata et al. 1311 (2006). 3,997,659 A 12/1976 Knohl et al. 4,146,611 A 3, 1979 Ondetti et al. (Continued) 4,379,177 A 4/1983 McCoy et al. 4,743,614 A 5, 1988 Terano et al. Primary Examiner — Rei-tsang Shiao 5,500,436 A 3/1996 Schonafinger et al. (74) Attorney, Agent, or Firm — Booth Udall Fuller, PLC 5,679,704 A 10/1997 Schonafinger et al. 7,235,237 B2 6/2007 Loscalzo et al. (57) ABSTRACT 8, 178,572 B2 * 5/2012 Kramer et al...... 514,400 8,183,288 B2 * 5/2012 Kramer et al...... 514,561 Methods for increasing athletic performance, distribution of 2002/01 19933 A1 8, 2002 Butler et al. various Amino to muscles, and solubility of various 2003/01 19888 A1 6, 2003 Allen 2005/0287210 A1 12, 2005 Ron Amino Acids in a humanoranimal by administering an amino 2005/0288372 A1 12, 2005 Ron acid composition that includes: at least one constituent 2005/0288373 A1 12, 2005 Ron selected from the group consisting of a nitrate, a nitrite, and 2006, OO29668 A1 2/2006 Ron both; and at least one constituent selected from the 2006, O1828.15 A1 8, 2006 Gladwin et al. group consisting of , , Beta , Cit 2007/O154569 A1 7/2007 Gladwin et al. rulline, Creatine, , L-, , Leu FOREIGN PATENT DOCUMENTS cine, Norvaline, , , , , CN 1631539 6, 2005 , , , , , and Pheny EP 13366O2 8, 2003 lalanine. GB 2354441 3, 2001 WO WO2006124161 4/2005 60 Claims, No Drawings US 8,466,187 B2 Page 2

OTHER PUBLICATIONS B. Sridhar, et al. “L-Aspartic Acid Nitrate-L-Aspartic Acid'. Acta Crystallographica Section, Dec. 2002, pp. 1372-1374, vol. 58. Fayers et al., "Nitrate tolerance and the links with endothelial dys B. Sridhar, etal, “Bis(beta-alanine) HydrogenNitrate'. Acta Crystal function and oxidative stress.” Blackwell Publishing Ltd Br. J. Clin. lographica Section, 2001, pp. 1004-1006, vol. 57. S. Narasinga Rao, et al., “Structure and Conformational Aspects of Pharmacol. vol. 56:620-628 (2003). the Nitrates of Amino Acids and . I. Crystal Structure of Harm J. Knot. “Nitrate Tolerance in Hypertension New Insight Into a Glycylglycine Nitrate”. Acta Crystallographica Section, 1973, pp. Century-Old Problem.” Circulation Research vol. 93:799-801 2379-2388, vol. 29. (2003). Bauer JA, et al., “Photochemical Generation of Nitric Oxide from Schulz et al., “Functional and Biochemical Analysis of Endothelial Nitro-containing Compounds: Possible Relation to Vascular (Dys)function and NO?cGMP Signaling in Human Blood Vessels Photorelaxation Phenomena', Life Science, 1994, 54, 1, PL 1-4. With and Without Nitroglycerin Pretreatment.” Circulation Research Mostad et al., 1986, CAS: 104-197543. vol. 105: 1170-1175 (2002). Pradhan et al. publication, Journal of Chemical and Engineering Hatanaka et al., “Stereoselective Pharmacokinetics and Data, 2000, 45(1): 140-143. Pharmacodynamics of Organic Nitrates in Rats,” J Pharmacol Exp Ramaswamy et al., “Vibrational Spectroscopic Studies of Ther. vol. 298(1):346-53 (2001). L-argininium dinitrate'. Journal of Raman Spectroscopy 2003. p. Chabot et al., “Characterization of the vasodilator properties of 50-56. vol. 34. www.interscience.wiley.com. peroxynitrite on rat pulmonary artery: role of poly ( Rajkumar and Ramakrishnan, “Infrared and Roman Spectra of 5'-diphosphoribose) synthase.” British Journal of Pharmacology vol. L-Valine Nitrate and L- Nitrate”, Journal of Raman Spec 121:485-490 (1997). troscopy, 2000. p. 1107-1112, vol. 31. John Wiley & Sons, Ltd. Bauer et al., “Vascular and Hemodynamic Differences between Petrosyan et al. “L-Histidine nitrates”, Journal of Molecular Struc Organic Nitrates and Nitrites.” The Journal of Pharmacology and ture, 2006. p. 160-167, vol. 794. www.sciencedirect.com. Experimental Therapeutics JPET vol. 280:326-331 (1997). Magg, G.W., Hecker, R.J. and Whitaker, P.A., “Nitrogenous Com Niu et al., Eur J. Pharmacol 580: 169-174 (2008). pounds in Sugarbeet Juices'. Journal of the American Society of Tan et al., Vasc Pharmacol 46:338.345 (2007). Technologists, 1972; vol. 17. No. 2, pp. 154-164. Ahtee et al., J. Nutr 116:2555-2556 (1986). Bloomer et al., J Int Soc Sports Nutr 4(22): 1-6 (2007). * cited by examiner US 8,466,187 B2 1. 2 AMINO ACID COMPOSITIONS of an amino acid composition including a nitrate or nitrite or both mixed with at least one amino acid selected from the CROSS REFERENCE TO RELATED group consisting of Arginine, Agmatine, Beta Alanine, Cit APPLICATIONS rulline, Creatine, Glutamine, L-Histidine, Isoleucine, Leu cine, Norvaline, Ornithine, Valine, Aspartic Acid, Cysteine, This application is a continuation-in-part application of the Glycine, Lysine, Methionine, Proline, Tyrosine, and Pheny earlier U.S. Utility patent application to Ronald Kramer, et. lalanine. al. entitled “Amino Acid Compounds, application Ser. No. The foregoing and other aspects, features, and advantages 12/336,938, filed Dec. 17, 2008, now pending, which is a will be apparent to those artisans of ordinary skill in the art continuation application of the earlier U.S. Utility patent 10 from the DESCRIPTION and DRAWINGS, and from the application to Ronald Kramer, et. al. entitled “Amino Acid CLAIMS. Compounds.” application Ser. No. 11/950,273, filed Dec. 4, 2007, now U.S. Pat. No. 7,777,074, which application claims DESCRIPTION the benefit of the filing date of U.S. Provisional Patent Appli cation 60/973.229 entitled “Amino Acid Compounds to 15 Overview, Terminology and Definitions: Ronald Kramer, et. al., filed on Sep. 18, 2007, the disclosures In describing implementations of an Amino Acid Com of all of which being hereby incorporated entirely herein by pound and Composition, the following terminology will be reference. used in accordance with the definitions and explanations set out below. Notwithstanding, other terminology, definitions, BACKGROUND and explanations may be found throughout this document, as well. 1. Technical Field As used herein, “Amino Acid' is a term used in its broadest Aspects of this document relate generally to amino acid sense and may refer to an Amino Acid in its many different compositions. chemical forms including a single administration Amino 2. Background 25 Acid, its physiologically active salts or esters, its combina It is desirable to design new amino acid compositions that tions with its various salts, its tautomeric, polymeric and/or have properties lacking in conventional amino acids, conven isomeric forms, its analog forms, its derivative forms, its tional nitrates, and conventional nitrites alone. products of , and/or its decarboxylation prod ucts. Amino Acids comprise, by way of non-limiting SUMMARY 30 example: Agmatine, Beta Alanine, Arginine, , Aspartic Acid, Cysteine, Glutamine, , Glycine, In one aspect, an amino acid composition is disclosed Histidine, L-Histidine, Leucine, Isoleucine, Lysine, Methion including a nitrate or nitrite or both mixed with at least one ine, PhenylBeta Alanine, Proline, . , Tryp amino acid selected from the group consisting of Arginine, tophan, Tyrosine, Valine, Citrulline, Creatine, Glutamine, Agmatine, Beta Alanine, Citrulline, Creatine, Glutamine, 35 L-Histidine, Isoleucine, Leucine, Norvaline, Ornithine, Norvaline, Ornithine, and . Valine, Aspartic Acid, Cysteine, Glycine, Lysine, Methion Compounds containing both a carboxyl group and an ine, Proline, Tyrosine, and Phenylalanine. amino group are typically known as Amino Acids. Amino The Amino Acid Composition may further include a phar Acids typically have the basic formula X-R, wherein X is: maceutically acceptable additive. The additive may be a car 40 rier, an excipient, a binder, a colorant, a flavoring agent, a CH-COOH preservative, a buffer, a dilutant, and/or combinations thereof. The Amino Acid Composition may be in the form of a cap Sule, tablet, pill, liquid, liquid Suspension, vapor, gas, powder, granulate or pulverulence. 45 Amino Acids typically differ from one another with respect In another aspect, a method is disclosed for enhancing to the structure of the R group. It is the structure of the R group athletic performance. The method includes administering a that typically determines the individuality and character of pharmaceutically effective amount to a humanoranimal of an each Amino Acid. amino acid composition including a nitrate or nitrite or both For example, the R group for the Amino Acid Arginine is: mixed with at least one amino acid selected from the group 50 consisting of Arginine, Agmatine, Beta Alanine, Citrulline, Creatine, Glutamine, L-Histidine, Isoleucine, Leucine, Nor valine, Ornithine, Valine, Aspartic Acid, Cysteine, Glycine, HN-CH-CH-CH Lysine, Methionine, Proline, Tyrosine, and Phenylalanine. CNH In still another aspect, a method is disclosed for increasing 55 distribution of Amino Acids to muscles. The method includes administering a pharmaceutically effective amount to a human or animal of an amino acid composition including a Arginine is characterized as a nonessential Amino Acid. nitrate or nitrite or both mixed with at least one amino acid Specifically, Arginine can be independently manufactured by selected from the group consisting of Arginine, Agmatine, 60 the human body, and does not need to be obtained directly Beta Alanine, Citrulline, Creatine, Glutamine, L-Histidine, through dietary intake. Arginine plays a significant role in Isoleucine, Leucine, Norvaline, Ornithine, Valine, Aspartic healing, cell division, immune function, the elimination of Acid, Cysteine, Glycine, Lysine, Methionine, Proline, from the body and the release of hormones. Argin Tyrosine, and Phenylalanine. ine is presently used in the industry to In even another aspect, a method is disclosed for increasing 65 Supplement Arginine production in the body. Arginine is also solubility of Amino Acids. The method includes administer presently used in the dietary Supplement industry to boost ing a pharmaceutically effective amount to a human or animal Human Growth Hormone (HGH) production, increase US 8,466,187 B2 3 4 vasodilation, enhance blood circulation, increase oxygen ability and limits the forms in which Glutamine may be effec flow to the muscles, and boost Nitric Oxide (NO) production. tively used. Additionally, Glutamine inhibits Nitric Acid Various Supplemental Arginine forms are available in the (NO) production through downregulation of eNOS synthase. consumer marketplace. The R group for the Amino Acid Leucine is: The vasodilating effect of ingested Arginine takes consid erable time to manifest since Arginine requires extensive to yield Nitric Oxide (NO). Additionally, consid erable amounts of Arginine are required to produce a signifi cant vasodilating effect, with common doses ranging from eight to twenty-four grams per day. 10 The R group for the Amino Acid Citrulline is: Leucine is an , meaning that Leucine is not synthesized in vivo in animals. Accordingly, Leucine 15 must be ingested, usually as a component of con O H Sumed directly through dietary intake. Leucine plays a sig nificant role in muscle synthesis. Leucine can also Citrulline is an alpha-Amino Acid naturally occurring in inhibit protein degradation in skeletal muscle, as well as in the the human body, and does not need to be obtained directly liver. Leucine is presently used in the dietary Supplement through dietary intake. In vivo, Citrulline is made from the industry to Supplement dietary Leucine sources. Leucine is Amino Acid Ornithine, along with in also presently used in the dietary Supplement industry to one of the central reactions in the . Citrulline is promote and stimulate muscle protein synthesis. also produced during the metabolism of Arginine in the body. Leucine, by itself, has no vasodilating properties. Leucine is Citrulline is presently used in the dietary supplement industry also water insoluble, which reduces its bioavailability and to supplement Citrulline production in the body. By itself, 25 limits the forms in which Leucine may be effectively used. Citrulline has no vasodilating properties. Citrulline is also water insoluble, which reduces its bioavailability and limits The R group for the Amino Acid Norvaline is: the forms in which Citrulline may be effectively used. The R group for the Amino Acid Creatine is: 30 N-1 n X

HN H Norvaline is a nonessential Amino Acid. Specifically, Nor )= NM Valine can be independently manufactured by the human -N 35 body, and does not need to be obtained directly through dietary intake. Norvaline is presently used in the dietary Supplement industry to Supplement Norvaline production in Creatine is a nonessential Amino Acid and is also a nitrog the body. Norvaline is also presently used in the dietary enous organic acid. Creatine is independently manufactured Supplement industry to inhibit the arginase and thus by the human body, and does not need to be obtained directly 40 reduce the conversion of Arginine to urea. Norvaline, by through dietary intake. Creatine plays a significant role in itself, has no vasodilating properties, although it enhances the providing muscles with energy. Creatine is presently used in vasodilating properties of Arginine. Norvaline is also water the dietary Supplement industry to Supplement Creatine pro insoluble, which reduces its bioavailability and limits the duction in the body. Creatine is also presently used in the forms in which Leucine may be effectively used. dietary Supplement industry to increase muscle-mass gains, 45 The R group for the Amino Acid Ornithine is: improve athletic performance and strength. Creatine, by itself, has no vasodilating properties. Creatine is also water insoluble, which reduces its bioavailability and limits the 2N-1- forms in which Creatine may be effectively used. 50 The R group for the Amino Acid Glutamine is: Hoc1NH,

Ornithine is a non-essential Amino Acid. That is, Ornithine O 55 is independently manufactured by the human body, and does not need to be obtained directly through dietary intake. Orni Glutamine is a nonessential Amino Acid. Glutamine is the thine plays a significant role in the synthesis of polyamines, most abundant naturally occurring, non-essential amino acid specifically via the action of . Orni in the human body and is found circulating in the blood, as thine is presently used in the dietary Supplement industry to well as stored in the skeletal muscles. Glutamine plays a 60 Supplement dietary Ornithine sources. Ornithine is also pres significant role in protein synthesis, muscle growth, and ently used in the dietary Supplement industry to enhance the wound healing. Glutamine is presently used in the dietary vasodilating properties in a series of products commonly Supplement industry to Supplement Glutamine production in known as “NO Boosters.” Ornithine exerts its vasodilating the body. Glutamine is also presently used in the dietary effect only by in vivo conversion to Arginine and then by Supplement industry to maintain the body's Glutamine pool. 65 following the pathway that converts Arginine to Nitric Acid Glutamine, by itself, has no vasodilating properties. (NO). Many grams of Ornithine, and a considerable amount Glutamine is also water insoluble, which reduces its bioavail of time, are required in order to assert its vasodilating effect. US 8,466,187 B2 5 6 The R group for the Amino Acid Histidine is: dients (chemical species presentina system) which have been combined (not necessarily in fixed proportions and not nec essarily with chemical bonding and not necessarily so that N each Substance retains its own chemical identity). Mixtures ( can be the product of a blending or mixing of chemical Sub N stances like elements and compounds, without chemical H bonding or other chemical change, so that each ingredient Substance retains its own chemical properties and makeup. Histidine is a naturally-occurring Amino Acid and is coded Mixtures can be either homogeneous or heterogeneous. A for in DNA. Relatively small shifts in cellular pH will change 10 homogeneous mixture is a type of mixture in which the com the electrical charge of Histidine. For this reason, Histidine position is uniform. A heterogeneous mixture is a type of finds its way into considerable use as a coordinating in mixture in which the composition can easily be identified, as , and also as a catalytic site in certain there are two or more phases present. A homogeneous mix . Histidine is currently used in the dietary Supple 15 ture in which there is both a solute and solvent present is also ment industry to Support carnosine production. Histidine, by a solution. itself, has no vasodilating properties. Additionally, Histidine A“Compound is a term used in its broadest sense and may is very poorly water soluble, a fact that limits its bioavailabil refer to a chemical Substance comprising two or more differ ity and utility. Histidine is presently used in the dietary ent chemically bonded chemical constituent elements or Supplement industry in the forms of single administration ingredients, with a fixed ratio or proportion by weight. The Histidine and Histidine HC1. atoms within a compound can be held together by a variety of The R group for the Amino Acid Beta Alanine is: interactions, ranging from covalent bonds to electrostatic forces inionic bonds. The physical and chemical properties of compounds are different from those of their constituent ele 25 ments. This is one of the main criteria for distinguishing a compound from a mixture of elements or other substances because a mixture's properties are generally closely related to Beta Alanine is the only naturally-occurring Beta Amino and dependent on the properties of its constituents. However, Acid. A Beta Amino Acid is one in which the Amino group is Some mixtures are so intimately combined that they have located at the beta position (i.e. two atoms away) from the 30 Some properties similar to compounds. Another criterion for Carboxyl group. Beta Alanine is formed in vivo through the distinguishing a compound from a mixture is that the con degradation of dihydrouracil and carnosine. Beta Alanine is stituents of a mixture can usually be separated by simple, the rate-limiting precursor of carnosine. Therefore, carnosine mechanical means such as filtering, evaporation, or use of a levels are limited by the amount of available Beta Alanine. magnetic force, but the components of a compound can only Beta Alanine, by itself, has no vasodilating properties. Addi 35 be separated by a chemical reaction. Conversely, mixtures tionally, Beat Alanine is somewhat water soluble, which lim can be created by mechanical means alone, but a compound its its bioavailability and utility. Beta Alanine is presently can only be created (either from elements or from other com used in the dietary Supplement industry to Support carnosine pounds, or a combination of the two) by a chemical reaction. production. Thus, for purposes of this disclosure, “Composition” may The chemical structure of Agmatine is: 40 refer to a mixture of at least one Amino Acid in combination with at least a Nitrate, a Nitrite, or both from any source. As used herein, "Nitrate' is a term used in its broadest sense and may refer to an Nitrate in its many different chemi cal forms including a of Nitric Acid, a single administra 45 tion Nitrate, its physiologically active salts or esters, its com binations with its various salts, its tautomeric, polymeric and/or isomeric forms, its analog forms, and/or its derivative Agmatine is the decarboxylation product of the Amino forms. Nitrate comprises, by way of non-limiting example, Acid Arginine and is an intermediate in polyamine biosyn many different chemical forms including dinitrate and trini thesis. Agmatine is synthesized in the brain and stored in 50 trate. Nitrates may be salts, or mixed salts, of Nitric Acid synaptic vesicles in regionally selective . Agmatine is (HNO) and comprise one Nitrogen atom and three Oxygen released by depolarization and is inactivated by agnatinase. atoms (NO). For the exemplary purposes of this disclosure, Agmatine binds to alpha2-adrenoceptors and imidazoline Nitrate may comprise salts of Nitrate such as sodium nitrate, binding sites. Agmatine likewise blocks N-methyl-D-aspartic potassium nitrate, barium nitrate, nitrate, and the acid (NMDA) receptor channels and other ligand-gated cat 55 like. For the exemplary purposes of this disclosure, Nitrate ionic channels. Additionally, agmatine inhibits nitric oxide may include mixed salts of Nitrate such as nitrate orotate, and synthase, and induces the release of some hormones. the like. Additionally, for the exemplary purposes of this Agmatine modulates nitric oxide through various mecha disclosure, Nitrate may comprise nitrate esters such as nitro nisms. Agmatine stimulates some types of nitric oxide Syn glycerine, and the like. Furthermore, for the exemplary pur thase (NOS) while inhibiting others. Agmatine inhibits Nitric 60 poses of this disclosure, nitrates that are commonly used in Oxide production by inhibiting NOS. Agmatine is presently Supplement industry are appropriate Sources of nitrates, such used in the dietary Supplement industry in the forms of single as juice, extract, powder and the like of Cabbage, Spinach, administration Agmatine and Agmatine Sulfate. Beetroot, Artichoke, , Broad Bean, Eggplant, Gar As used herein, “Composition' is a term used in its broad lic, Onion, Green Bean, Mushroom, Pea, Pepper, Potato, est sense and may refer to a mixture of constituent Substances 65 Summer Squash, Sweet Potato, Tomato, Watermelon, Broc or ingredients. “Mixture' is a term used in its broadest sense coli, Carrot, Cauliflower, Cucumber, Pumpkin, Chicory, Dill, and may refer to two or more constituent Substances or ingre Turnip, Savoy Cabbage, Celeriac, Chinese Cabbage, Endive, US 8,466,187 B2 7 8 Fennel, Kohlrabi, Leek, Parsley, Celery, Cress, Chervil, Let macopeial Standards (USP), US Department of Agriculture tuce, Rocket (Rucola), and the like. (USDA) standards for food-grade materials, commonly As used herein, "Nitrite' is a term used in its broadest sense accepted Standards of the nutritional Supplement industry, and may refer to an Nitrite in its many different chemical industry standards, botanical standards, or standards estab forms including a salt of Nitrous Acid, a single administration lished by any individual. These standards may delineate Nitrite, its physiologically active salts or esters, its combina acceptable ranges of aspects of ingredients of a pharmaceu tions with its various salts, its tautomeric, polymeric and/or tical composition such as edibility, toxicity, pharmacological isomeric forms, its analog forms, and its derivative forms. effect, or any other aspect of a chemical, composition, or Nitrite comprises, by way of non-limiting example, many preparation used in implementations of a pharmaceutical different chemical forms including dinitrite and trinitrite. 10 composition. Nitrites may be salts, or mixed salts, of Nitrous Acid (HNO) and comprise one Nitrogen atom and two Oxygen atoms Components/Compounds/Compositions (NO). For the exemplary purposes of this disclosure, Nitrite A first implementation is an Arginine compound of the may comprise salts of Nitrite such as sodium nitrite, potas formula: sium nitrite, barium nitrite, calcium nitrite, and the like. For 15 the exemplary purposes of this disclosure, Nitrite may com prise mixed salts of Nitrite such as nitrite orotate, and the like. Additionally, for the exemplary purposes of this disclosure, Nitrite may comprise nitrite esters such as amyl nitrite, and the like. Furthermore, for the exemplary purposes of this disclosure, natural Sources of Nitrites that are commonly used in Supplement industry are appropriate sources of Nitrites, wherein; Such as juice, extract, powder and the like of Cabbage, Spin R is the Arginine group identified and defined above: ach, Beetroot, Artichoke, Asparagus, Broad Bean, Eggplant, X is the Amino Acid base identified and defined above; and Garlic, Onion, Green Bean, Mushroom, Pea, Pepper, Potato, 25 Summer Squash, Sweet Potato, Tomato; Watermelon, Broc Y is selected from the group consisting of a Nitrate and a coli, Carrot, Cauliflower, Cucumber, Pumpkin, Chicory, Dill, Nitrite. Turnip, Savoy Cabbage, Celeriac, Chinese Cabbage, Endive, Applicants have cost-effectively synthesized Arginine Fennel, Kohlrabi, Leek, Parsley, Celery, Cress, Chervil, Let Nitrate by combining nitric acid and Arginine, mixing with tuce, Rocket (Rucola), and the like. 30 water or another polar, easily evaporated solvent like metha Nitrates and Nitrites are commercially available in various nol, , , and the like, and leaving to crystallize. preparations, including natural preparations, and are used in Further nitratization can take place, yielding Arginine Dini various applications. In the case of ingestion by humans, trate or Arginine Trinitrate. An alternative implementation Nitrate (NO) is typically reduced to Nitrite (NO) in the may comprise using Nitrous Acid (HNO) instead of Nitric epithelial cells of blood vessels. In vivo, Nitrite (NO) reacts 35 with a thiol donor, principally , to yield Nitric Acid (HNO), thus yielding Arginine Nitrite. Arginine Nitrite Oxide (NO). has the same effects as Arginine Nitrate, the only difference As used herein, “pharmaceutically acceptable additive' or being that it requires one less step to yield Nitric Oxide “additive' are terms used in their broadest sense. Particular (NO—). Mixed salts may also be used, such as in the non implementations of the compositions described in this docu 40 limiting example of Arginine Nitrate-Orotate. ment may also comprise an additive (e.g. one of a solubilizer, A second implementation is a Citrulline compound of the an enzyme inhibiting agent, an anticoagulant, an antifoaming formula: agent, an antioxidant, a coloring agent, a coolant, a cryopro tectant, a bonding agent, a flavoring agent, a plas ticizer, a preservative, a Sweetener, a thickener, and combina 45 R tions thereof) and/or a carrier (e.g. one of an excipient, a || Y. lubricant, a binder, a disintegrator, a diluent, an extender, a X Solvent, a suspending agent, a dissolution aid, an isotoniza tion agent, a buffering agent, a Soothing agent, an amphip athic delivery system, and combinations thereof). These 50 wherein; additives may be solids or liquids, and the type of additive R is the Citruline group identified and defined above: may be generally chosen based on the type of administration being used. Those of ordinary skill in the art will be able to X is the Amino Acid base identified and defined above; and readily select suitable pharmaceutically effective additives Y is selected from the group consisting of a Nitrate and a Nitrite. from the disclosure in this document. In particular implemen 55 tations, pharmaceutically acceptable additives may include, Applicants have cost-effectively synthesized Citrulline by non-limiting example, calcium phosphate, cellulose, Nitrate by combining nitric acid and Citruline, mixing with Stearic acid, croScarmelose cellulose, Stearate, water or another polar, easily evaporated solvent like metha and silicon dioxide. nol, alcohol, pyridine, and the like, and leaving to crystallize. As used in this document, “pharmaceutically effective' is a 60 Further nitratization can take place, yielding Citrulline Dini phrase used in its broadest sense, including, by non-limiting trate or Citrulline Trinitrate. An alternative implementation example, effective in a clinical trial, for a specific patient, or may comprise using Nitrous Acid (HNO) instead of Nitric only placebo-effective. Acid (HNO), thus yielding Citrulline Nitrite. Citrulline As used in this document, “Pharmaceutically acceptable' Nitrite has the same effects as Citrulline Nitrate, the only is a phrase used in its broadest sense and may describe ingre 65 difference being that it requires one less step to yield Nitric dients of a pharmaceutical composition that meet Food and Oxide (NO-). Mixed salts may also be used, such as in the Drug Administration (FDA) standards, United States Phar non-limiting example of Citrulline Nitrate-Orotate. US 8,466,187 B2 9 10 A third implementation is a Creatine compound of the Applicants have cost-effectively synthesized Leucine formula: Nitrate by combining nitric acid and Leucine, mixing with water or another polar, easily evaporated solvent like metha nol, alcohol, pyridine, and the like, and leaving to crystallize. Further nitratization can take place, yielding Leucine Dini trate or Leucine Trinitrate. An alternative implementation comprises Substituting the Amino Acids Valine or Isoleucine for Leucine. Another alternative implementation comprises wherein; substituting Nitrous Acid (HNO) for Nitric Acid (HNO), 10 thus yielding Leucine Nitrite. Leucine Nitrite has the same R is the Creatine group identified and defined above: effects as Leucine Nitrate, the only difference being that it X is the Amino Acid base identified and defined above; and requires one less step to yield Nitric Oxide (NO ). Mixed Y is selected from the group consisting of a Nitrate and a salts may also be used, such as in the non-limiting example of Nitrite. Leucine Nitrate-Orotate. Applicants have cost-effectively synthesized Creatine 15 A sixth implementation is a Norvaline compound of the Nitrate by combining nitric acid and Creatine, mixing with formula: water or another polar, easily evaporated solvent like metha nol, alcohol, pyridine, and the like, and leaving to crystallize. Further nitratization can take place, yielding Creatine Dini trate or Creatine Trinitrate. An alternative implementation may comprise using Nitrous Acid (HNO) instead of Nitric Acid (HNO), thus yielding Creatine Nitrite. Creatine Nitrite has the same effects as Creatine Nitrate, the only difference being that it requires one less step to yield Nitric Oxide wherein; (NO—). Mixed salts may also be used, such as in the non 25 R is the Norvaline group identified and defined above; limiting example of Creatine Nitrate-Orotate. X is the Amino Acid base identified and defined above; and A fourth implementation is a Glutamine compound of the Y is selected from the group consisting of a Nitrate and a formula: Nitrite. Applicants have cost-effectively synthesized Norvaline 30 Nitrate by combining nitric acid and Norvaline, mixing with water or another polar, easily evaporated solvent like metha nol, alcohol, pyridine, and the like, and leaving to crystallize. Further nitratization can take place, yielding Norvaline Dini trate or Norvaline Trinitrate. An alternative implementation 35 comprises substituting Nitrous Acid (HNO) for Nitric Acid wherein; (HNO), thus yielding Norvaline Nitrite. Norvaline Nitrite R is the Glutamine group identified and defined above: has the same effects as Norvaline Nitrate, the only difference X is the Amino Acid base identified and defined above; and being that it requires one less step to yield Nitric Oxide Y is selected from the group consisting of a Nitrate and a (NO—). Mixed salts may also be used, such as in the non Nitrite. 40 limiting example of Norvaline Nitrate-Orotate. Applicants have cost-effectively synthesized Glutamine A seventh implementation is an Ornithine compound of the Nitrate by combining nitric acid and Glutamine, mixing with formula: water or another polar, easily evaporated solvent like metha nol, alcohol, pyridine, and the like, and leaving to crystallize. Further nitratization can take place, yielding Glutamine Dini 45 trate or Glutamine Trinitrate. An alternative implementation comprises using Nitrous Acid (HNO) instead of Nitric Acid (HNO), thus yielding Glutamine Nitrite. Glutamine Nitrite has the same effects as Glutamine Nitrate, the only difference being that it requires one less step to yield Nitric Oxide 50 wherein; (NO—). Mixed salts may also be used, such as in the non R is the Ornithine group identified and defined above: limiting example of Glutamine Nitrate-Orotate. X is the Amino Acid base identified and defined above; and A fifth implementation is a Leucine compound of the for Y is selected from the group consisting of a Nitrate and a mula: 55 Nitrite. Applicants have cost-effectively synthesized Ornithine Nitrate by combining nitric acid and Ornithine, mixing with water or another polar, easily evaporated solvent like metha nol, alcohol, pyridine, and the like, and leaving to crystallize. 60 Further nitratization can take place, yielding Ornithine Dini trate or Ornithine Trinitrate. An alternative implementation wherein; comprises using Nitrous Acid (HNO) instead of Nitric Acid (HNO), thus yielding Ornithine Nitrite. Ornithine Nitrite has R is the Leucine group identified and defined above: the same effects as Ornithine Nitrate, the only difference X is the Amino Acid base identified and defined above; and 65 being that it requires one less step to yield Nitric Oxide Y is selected from the group consisting of a Nitrate and a (NO—). Mixed salts may also be used, such as in the non Nitrite. limiting example of Ornithine Nitrate-Orotate. US 8,466,187 B2 11 12 An eighth implementation is a Histidine compound of the nol, alcohol, pyridine, and the like, and leaving to crystallize. formula: Further nitratization can take place, yielding Agmatine Dini trate or Agmatine Trinitrate. An alternative implementation comprises using Nitrous Acid (HNO) instead of Nitric Acid (HNO), thus yielding Agmatine Nitrite. Agmatine Nitrite has the same effects as Agmatine Nitrate, the only difference being that it requires one less step to yield Nitric Oxide (NO—). Mixed salts may also be used, such as in the non wherein; limiting example of Agmatine Nitrate-Orotate. R is the Histidine group identified and defined above: 10 Other implementations involve compositions instead of X is the Amino Acid base identified and defined above; and compounds. Using an independent Source of nitrates and/or Y is selected from the group consisting of a Nitrate and a nitrites that is mixed with any of the amino acids disclosed in Nitrite. this document to form a composition can obtain Substantially Applicants have cost-effectively synthesized Histidine 15 the same effects as the amino acid nitrate or nitrite com Nitrate by combining nitric acid and Histidine, mixing with pounds discussed in this document. water or another polar, easily evaporated solvent like metha Such an amino acid composition might be depicted by the nol, alcohol, pyridine, and the like, and leaving to crystallize. formula X-R+Y. X-R represents an amino acid as dis Further nitratization can take place, yielding Histidine Dini cussed previously and “Y” represents a Nitrate and/or Nitrite. trate or Histidine Trinitrate. An alternative implementation But instead of forming a compound, they are mixed together comprises using Nitrous Acid (HNO) instead of Nitric Acid (represented by the "+”) to form a composition. (HNO), thus yielding Histidine Nitrite. Histidine Nitrite has For the exemplary purposes of this disclosure, following is the same effects as Histidine Nitrate, the only difference a variety of specific examples of amino acid compositions. being that it requires one less step to yield Nitric Oxide Composition 1: Creatine Nitrate 100-1000 mg in capsules. (NO—). Mixed salts may also be used, such as in the non 25 Dosage is 3 capsules twice daily. limiting example of Histidine Nitrate-Orotate. Composition 2 (Powder Form): Serving Size: 4 grams. A ninth implementation is a Beta Alanine compound of the Creatine Nitrate 3-3.5 grams. C 500-1000 mg. formula: Composition 3 (Sports Drink): 0.5-3 Grams Arginine Nitrate. 0.5-2 Grams . 1-3 grams Sugar or appropriate 30 Sweetener. Artificial Coloring. Purified Water till 500 ml of total Volume. Composition 4 (sublingual tablets; amounts are per tablet): Agmatine Nitrate 10-100 mg. Maltulose 200 mg. Artificial Cherry Flavor. Melt Maltulose, add in slowly the Agmatine wherein; 35 Nitrate and the flavor, and pour in the tablet machine. R is the Beta Alanine group identified and defined above: Composition 5 (Tablets Containing Arginine and Potas X is the Amino Acid base identified and defined above; and sium Nitrate for Blood Pressure support). Per tablet: Arginine Y is selected from the group consisting of a Nitrate and a 250-700 mg. Potassium Nitrate 50-500 mg. Corn Starch till Nitrite. the desired volume for the tablet machine is obtained. Applicants have cost-effectively synthesized Beta Alanine 40 Composition 6 (for healthy blood pressure support): 500 Nitrate by combining nitric acid and Beta Alanine, mixing 1000 mg Arginine (As arginine nitrate)+250-500 mg Celery with water or another polar, easily evaporated solvent like Seed Extract--100-300 mg Dried Garlic Powder in airseal methanol, alcohol, pyridine, and the like, and leaving to crys Capsules. tallize. Further nitratization can take place, yielding Beta Composition 7 (For improved Sexual Performance): 500 Alanine Dinitrate or Beta Alanine Trinitrate. An alternative 45 1000 mg grams Agmatine--1-2 grams D-aspartic Acid (as implementation comprises using Nitrous Acid (HNO) D-Aspartic Acid Nitrate)+1-2 grams dried onion powder (on instead of Nitric Acid (HNO), thus yielding Beta Alanine ion also increases testosterone) in capsules. Nitrite. Beta Alanine Nitrite has the same effects as Beta Composition 8 (Improved Strength): Creatine(As Creatine Alanine Nitrate, the only difference being that it requires one Malate) 2-3 grams and Calcium Nitrate 500 mg. less step to yield Nitric Oxide (NO ). Mixed salts may also 50 Composition 9 (Improved Muscle Endurance Sports be used. Such as in the non-limiting example of Beta Alanine Drink): Beta Alanine 1-2 grams+Citrulline (As Citrulline Nitrate-Orotate. Nitrate) 250-500 mg--Potassium Nitrate 100-200 mg--So A tenth implementation is an Agmatine compound of the dium Nitrate 50-100 mg-i-Magnesium Nitrate 200 mg Artifi formula: cial COlouring Sweetener and flavour Purified Water till 500 55 ml. Composition 10 (Improved Muscle anabolism and recov ery): Leucine 1-5 grams Isoleucine 1-2 grams Valine 1-2 HN 1-1N-Ns NH Y grams Spinach Extract (Standarized for nitrate content and NH2 ecdysterone content minimum 1% and 10% respectively) 5 60 grams. Composition 11 (Improved Mental Performance): wherein; 500-1000 mg Tyrosine--250-500 mg Phenylalanine (as Phe Y is selected from the group consisting of a Nitrate and a nylalanine Nitrate)+1000-2000 mg Glycine-200-300 mg Nitrite. Lithium Nitrate+300-600mg Hystidine InTime Release Tab Applicants have cost-effectively synthesized Agmatine 65 lets. Nitrate by combining nitric acid and Agmatine, mixing with Composition 12 (Growth Hormone Support): Arginine 2-4 water or another polar, easily evaporated solvent like metha grams+Ornithine 1-2 grams+Magnesium Nitrate 500 mg. US 8,466,187 B2 13 14 Composition 13 (Hair Growth Support As External Use any additional pharmaceutically acceptable additives or inert Cream): Lysine Nitrite 1 gram Hydroxyproline Nitrate 5 ingredients, and then separating the pharmaceutical compo grams Methionine nitrate 5 grams Euserine Cream Base 100 sition into discrete quantities for distribution and/or admin grams. istration. Composition 14 (Immune Support effervescent tabs): Measuring specific quantities of Amino Acid, Nitric or Glutamine 400-800 mg Hystidine (As histidine nitrate) 250 Nitrous Acid and water or solvent, and pharmaceutically 500 mg. Cysteine (As N-Acetyl Cysteine) 200-300 mg PArs acceptable additives or inert ingredients, may involve any ley Powder (Standarized for Vitamin C and nitrate) 125-250 number of steps and implementing components, and measur ng. ing specific quantities of Amino Acid, Nitric or Nitrous Acid Administration and Dosage Forms 10 and water or solvent, and pharmaceutically acceptable addi Compounds, Compositions and/or formulations may be tives or inert ingredients, may be accomplished readily from administered in any form, including one of a capsule, a this disclosure. For the exemplary purposes of this disclosure, cachet, a pill, a tablet, a powder, a granule, a pellet, a bead, a measuring specific quantities of Amino Acid, Nitric or particle, a troche, a lozenge, a pastille, a Solution, an elixir, a Nitrous Acid and water or solvent, and pharmaceutically syrup, a tincture, a suspension, an emulsion, a mouthwash, a 15 acceptable additives or inertingredients, may comprise using spray, a drop, an ointment, a cream, a gel, a paste, a transder a scale, a solid or liquid dispensing apparatus, or other mea mal patch, a Suppository, a pessary, cream, a gel, a paste, a Surement device capable of measuring Solid mass or liquid foam, and combinations thereof for example. Volume to produce a desired quantity of Amino Acid, Nitric or Implementations of Amino Acid Compounds and Compo Nitrous Acid and water or solvent, and pharmaceutically sitions may conveniently be presented in unit dosage form. acceptable ingredient. Unit dosage formulations may be those containing a daily It should be appreciated that any of the components of dose or unit, a daily Sub-dose, or an appropriate fraction particular implementations of an Amino Acid Compound or thereof, of the administered components as described herein. Composition may be used as Supplied commercially, or may A dosage unit may include an Amino Acid Compound or be preprocessed by, by non-limiting example, any of the Composition. In addition, a dosage unit may include an 25 methods and techniques of agglomeration, air Suspension Amino Acid Compound or Composition admixed with a chilling, air Suspension drying, balling, coacervation, com pharmaceutically acceptable additive(s), and/or any combi minution, compression, pelletization, cryopelletization, nation thereof. extrusion, granulation, homogenization, inclusion Compoun The dosage units may be in a form suitable for administra dation, lyophilization, melting, mixed, molding, pan coating, tion by standard routes. In general, the dosage units may be 30 Solvent dehydration, Sonication, spheronization, spray chill administered, by non-limiting example, by the topical (in ing, spray congealing, spray drying, or other processes known cluding buccaland sublingual), transdermal, oral, rectal, oph in the art depending in part on the dosage form desired. The thalmic (including intravitreal or intracameral), nasal, vagi various components may also be pre-coated or encapsulated nal, and/or parenteral (including Subcutaneous, as known in the art. It will also be clear to one of ordinary skill intramuscular, intravenous, intradermal, intratracheal, and 35 in the art that appropriate additives may also be introduced to epidural) routes and many other delivery methods and/or the composition or during the processes to facilitate the systems known to those of ordinary skill in the art. Imple preparation of the dosage forms, depending on the need of the mentations of an Amino Acid Compound or Composition individual process. may also be administered through use of amphipathic lipid Mixing the measured quantities of Amino Acid, Nitric or delivery systems (such as liposomes and unilamellar 40 Nitrous Acid and water or solvent, and pharmaceutically vesicles). Those of ordinary skill in the art will readily be able acceptable additives or inert ingredients for Compounds, or to select additional pharmaceutically acceptable additives to mixing the measured quantities of Amino Acid, Nitrate and/or enable delivery of implementations of a pharmaceutical com Nitrite sources, and pharmaceutically acceptable additives or position from the disclosure in this document. inert ingredients for Compositions, may involve any number For the exemplary purposes of this disclosure, oral delivery 45 of steps and implementing components, and may be accom may be a particularly advantageous delivery route for admin plished readily from this disclosure. istration to humans and animals of implementations of a For the exemplary purposes of this disclosure, mixing the pharmaceutical composition, optionally formulated with measured quantities of Amino Acid, Nitric or Nitrous Acid appropriate pharmaceutically acceptable additives to facili and water or solvent, and pharmaceutically acceptable addi tate administration. 50 tives or inert ingredients, may comprise combining the mea Manufacture sured quantities of m Amino Acid, Nitric or Nitrous Acid and Implementations of Amino Acid Nitrate and/or Nitrite water or solvent, and pharmaceutically acceptable additives Compounds or Compositions may be synthesized or created or inert ingredients, under the influence of physical, ultra in a wide variety of manners, and may be made from a wide Sonic, or electrostatic forces to create a desired degree of variety of materials. Those of ordinary skill in the art will 55 intermingling and/or chemical reaction of the Amino Acid, readily be able to select appropriate materials and methods to Nitric or Nitrous Acid and water or solvent and any pharma manufacture and use the compounds and compositions dis ceutically acceptable ingredients. The mixed may be accom closed herein. plished when the Amino Acid, Nitric or Nitrous Acid and Accordingly, although there are a variety of method imple water or solvent and/or any pharmaceutically acceptable mentations for producing pharmaceutical compositions, for 60 ingredients are in a solid, liquid, or semisolid state. the exemplary purposes of this disclosure, a method imple Separating the Amino Acid Compound or Composition mentation for producing an Amino Acid Compound may into discrete quantities for distribution may involve any num comprise: measuring specific quantities of Amino Acid, ber of steps and implementing components, and separating Nitric or Nitrous Acid and water or any other polar, easily the Amino Acid Compound or Composition into discrete evaporated Solvent Such as methanol, alcohol, pyridine, and 65 quantities for distribution may be accomplished readily from the like mixed in a specific order the measured quantities of this disclosure. For the exemplary purposes of this disclosure, Amino Acid, Nitric or Nitrous Acid and water or solvent, and separating the Amino Acid Compound or Composition into US 8,466,187 B2 15 16 discrete quantities for distribution may involve utilizing a mannitol, magnesium Stearate, potassium chloride, and citric specific piece of equipment, for example, a conventional tab acid, among other organic and inorganic materials. let forming apparatus to shape the formed composition into Buffering agents may be included in an Amino Acid Com individual tablets, each containing a desired dose of Amino pound or Composition and may be any one of an acid and a Acid Compound or Composition. The separating process 5 base, where the acid is, for example, propionic acid, p-tolu may be accomplished when the Amino Acid Compound or enesulfonic acid, salicylic acid, Stearic acid, Succinic acid, Composition is in a Solid, liquid, or semisolid state. tannic acid, tartaric acid, thioglycolic acid, or toluenesulfonic Those of ordinary skill in the art will be able to readily acid, and the base is, for example, ammonium hydroxide, select manufacturing equipment and pharmaceutically potassium hydroxide, Sodium hydroxide, sodium hydrogen acceptable additives or inert ingredients to manufacture 10 implementations of an Amino Acid Compound or Composi carbonate, aluminum hydroxide, calcium carbonate, and tion. For the exemplary purposes of this disclosure, some other organic and inorganic chemicals. examples of pharmaceutically acceptable additives or inert With respect to delivery of particular implementations of ingredients and manufacturing process are included below, an Amino Acid Compound or Composition, for the exem particularly those that relate to manufacture of implementa- 15 plary purposes of this disclosure, tablets may be utilized. tions of an Amino Acid Compound or Composition in tablet Tablets are any solid pharmaceutical dosage form containing form. Notwithstanding the specific examples given, it will be a pharmaceutically acceptable active agent or agents to be understood that those of ordinary skill in the art will readily administered with or without suitable pharmaceutically appreciate how to manufacture implementations of an Amino acceptable additives and prepared either by compression or Acid Compound or Composition according to the other meth- 20 molding methods well known in the art. Tablets have been in ods of administration and delivery disclosed in this docu widespread use and remain popular as a dosage form because ment. of the advantages afforded both to the manufacturer (e.g., Accordingly, compounds and Compositions may include a simplicity and economy of preparation, stability, and conve acceptable additive (e.g. one of a solubilizer, an enzyme nience in packaging, shipping, and dispensing) and the inhibiting agent, an anticoagulant, an antifoaming agent, an 25 patient (e.g., accuracy of dosage, compactness, portability, antioxidant, a coloring agent, a coolant, a cryoprotectant, a blandness of taste, and ease of administration). Although hydrogen bonding agent, a flavoring agent, a plasticizer, a tablets are most frequently discoid in shape, they may also be preservative, a Sweetener, a thickener, and combinations round, oval, oblong, cylindrical, rectangular or triangular, for thereof) and/or a acceptable carrier (e.g. one of an excipient, example. The tablets may be optionally scored so that they a lubricant, a binder, a disintegrator, a diluent, an extender, a 30 may be separated into different dosages. They may differ Solvent, a suspending agent, a dissolution aid, an isotoniza greatly in size and weight depending on the amount of the tion agent, a buffering agent, a Soothing agent, an amphip pharmaceutically acceptable active agent or agents present athic lipid delivery system, and combinations thereof). and the intended route of administration. They are divided For example, a particular implementation of an Amino into two general classes, (1) compressed tablets, and (2) Acid Compound or Composition may include a lubricant. 35 molded tablets. Lubricants are any anti-sticking agents, glidants, flow pro Tablets and other orally discrete dosage forms, such as moters, and the like materials that perform a number of func capsules, cachets, pills, granules, pellets, beads, and particles, tions in tablet manufacture, for example, such as improving for example, may optionally be coated with one or more the rate of flow of the tablet granulation, preventing adhesion enteric coatings, seal coatings, film coatings, barrier coatings, of the tablet material to the surface of the dies and punches, 40 compress coatings, fast disintegrating coatings, or enzyme reducing interparticle friction, and facilitating the ejection of degradable coatings for example. Multiple coatings may be the tablets from the die cavity. Lubricants may comprise, for applied for desired performance. Further, dosage forms may example, magnesium Stearate, calcium Stearate, talc, and col be designed for, by non-limiting example, immediate release, loidal silica. pulsatile release, controlled release, extended release, Particular implementations of an Amino Acid Compound 45 delayed release, targeted release, synchronized release, or or Composition may also include a binder. Binders are any targeted delayed release. For release/absorption control, car agents used to impart cohesive qualities to powdered material riers may be made of various component types and levels or through particle-particle bonding. Binders may include, for thicknesses of coats. Such diverse carriers may be blended in example, matrix binders (e.g. dry starch, dry Sugars), film a dosage form to achieve a desired performance. In addition, binders (e.g. celluloses, bentonite. Sucrose), and chemical 50 the dosage form release profile may be effected by a poly binders (e.g. polymeric cellulose derivatives, such as methyl meric matrix composition, a coated matrix composition, a cellulose, carboxy methyl cellulose, and hydroxy propyl cel multi-particulate composition, a coated multi-particulate lulose); and other Sugar, , non-cellulosic binders and composition, an ion-exchange resin-based composition, an the like. osmosis-based composition, or a biodegradable polymeric Disintegrators may be used in particular implementations 55 composition. of an Amino Acid Compound or Composition to facilitate the While manufacture of implementations of an Amino Acid breakup or disintegration of tablets after administration. Dis Compound and Composition have been described in particu integrators may include, for example, starch, starch deriva lar sequences of steps and/or in particular forms, it will be tives, clays (e.g. bentonite), algins, gums (e.g. guar gum). understood that such manufacture is not limited to the specific cellulose, cellulose derivatives (e.g. methyl cellulose, car- 60 order of steps or forms as disclosed. Any steps or sequences of boxymethyl cellulose), croScarmellose sodium, croScarmel steps of manufacture of implementations of an Amino Acid lose cellulose, and other organic and inorganic materials. Compound and Composition in any form are given as Implementations of an Amino Acid Compound or Compo examples of possible steps or sequences of steps or potential sition may include diluents, or any inert Substances added to forms and not as limitations, since many possible manufac increase the bulk of the Amino Acid Compound to make a 65 turing processes and sequences of steps may be used to manu tablet a practical size for compression. Diluents may include, facture Amino Acid Compound and Composition implemen for example, calcium phosphate, calcium Sulfate, lactose, tations in a wide variety of forms. US 8,466,187 B2 17 18 Use nals in Human Muscle' available at http://jn.nutrition.org/ Implementations of an Amino Acid Compound or Compo cgi/content/full/136/1/264S, the contents of which are hereby sition are particularly useful in increasing bioabsorption and incorporated by reference. vasodilation in humans and animals. However, implementa Empirical studies indicate that the Amino Acids Beta-Beta tions are not limited to uses relating to bioabsorption or Alanine and L-Histidine Support carnosine production. M. vasodilation modification, and the like. Rather, any descrip Dunnett, “Influence of Oral Beta-Beta Alanine and L-Histi tion relating to the foregoing is for the exemplary purposes of dine Supplementation on the Carnosine Content of the Glu this disclosure. It will be understood that implementations of teus Medius' Equine Veterinary Journal Supplement, avail an Amino Acid Compound or Composition may encompass a able at http://www.ncbi.nlm.nih.gov/sites/entrez?Db= 10 pubmed&Cmd=ShowDetailView&TermToSearch= variety of uses and are not limited in their uses. For example, 10659307&ordinalpos=4&itool-EntrezSystem2.PEntrez. possible uses may be, by non-limiting example, prevention of Pubmed. Pubmed, the contents of which are hereby incorpo Nitrate tolerance, enhanced water solubility, increased distri rated by reference. bution to muscles, increased athletic performance, and/or Empirical studies further indicate that the Amino Acids countering Nitric Oxide inhibiting effects of certain Amino 15 Beta Alanine and L-Histidine increase muscle power, recu Acids. peration and stamina. Yoshihiro Suzuki “High Level of Skel In conventional preparations of Nitrate compounds, “tol etal Muscle Carnosine Contributes to the Latter Half of Exer erance a particular side effect, has been observed in many cise Performance During 30-S Maximal Cycle Ergometer patients. This is unfortunate because the effectiveness of Sprinting in the Japanese Journal of Physiology, available at Nitrate on vasodilation is well documented. “Tolerance' http://www.ncbi.nlm.nih.gov/sites/entrez?Db-pubmed& occurs when a Subjects reaction to Nitrate decreases so that Cmd=ShowDetailView&TermToSearch=12139778&ordinal larger doses are required to achieve the same effect. A Mar. 3, pos=4&itool-EntrezSystem2.PEntrez. Pubmed. Pubmed 2000 report in the British Journal of Pharmacology indicates ResultsPanel. Pubmed RVDocSum, the contents of which that “tolerance to the dilator effects of nitrates remains a are hereby incorporated by reference. persisting therapeutic problem.” Raymond J. MacAllister 25 Accordingly, Applicants have discovered that the Arginine Arginine and Nitrate Tolerance' available at http://www.na compound according to the first implementation, when ture.com/bjp/journal/v130/n2/full/0703340a.html, the con ingested, provides enhanced Nitric Oxide (NO ) production tents of which are hereby incorporated herein by reference. while providing improved vasodilation effects over single Empirical studies indicate that Nitrates are useful for their administration of Arginine, the single administration of vasolidating effects. Common Nitrates include nitroglycerin 30 Nitrates, or the single administration of Nitrites. Improved and isosorbide dinitrate. Nitrates exert their vasodilating vasodilation may, in turn, provide better circulation and dis effect through their reduction to Nitrites. In vivo, Nitrates are tribution of Arginine in the body. Absorption may be reduced to Nitrites and, in the blood vessels epithelial cells, improved since Amino Acid salts with inorganic acids are Nitrite reacts with a thiol donor (mainly glutathione) to yield much more water soluble than single administration Amino Nitric Oxide. Louis J. Ignarro, “After 130 years, the Molecu 35 Acids. Applicants have also discovered that the vasodilating lar Mechanism of Action of Nitroglycerin is Revealed’ (Jun. effect of Arginine Nitrate manifests faster than that of single 11, 2002) available at http://www.pnas.org/cgi/content/full/ administration Arginine, and as fast as any nitrate, since the 99/12/7816?ck inck, the contents of which are hereby incor NO-group of the salt requires minimal conversion to yield porated herein by reference. Nitric Oxide. Additionally a much lesser dose may be The Nitric Oxide inhibiting characteristics of the Amino 40 required for vasodilation to take place, compared to the single Acid Glutamine have been well documented in a number of administration of Arginine. Likewise, the development of studies. In particular, a Mar. 28, 2006 report in the American tolerance to the nitrate component of the molecule may be Journal of Physiology has found that Glutamine inhibits prevented with the presence of Arginine. Arginine Nitrate Nitric Oxide production by downregulation of eNOS syn may promote vasodilation through production of Nitric thase. Masao Kakoki, et al. “Amino acids as Modulators of 45 Oxide by two different pathways, the Arginine citrullization Endothelium-Derived Nitric Oxide.” available at http://ajpre pathway and the nitrate reduction pathway. Arginine Nitrate nal physiology.org/cgi/content/full/291/2/F297, the contents may likewise be more water Soluble than single administra of which are hereby incorporated by reference. tion Arginine. A January 2006 Journal of report indicates that Accordingly, Applicants have discovered that the Citrul the Amino Acid Leucine promotes anabolism and stimulates 50 line compound according to the second implementation, muscle protein synthesis. Michael J. Rennie, et al. when ingested, provides enhanced Nitric Oxide (NO ) pro “Branched-Chain Amino Acids as Fuels and Anabolic Sig duction while providing improved vasodilation effects over nals in Human Muscle' available at http://jn.nutrition.org/ single administration of Citrulline, the single administration cgi/content/full/136/1/264S, the contents of which are hereby of Nitrates, or the single administration of Nitrites. Improved incorporated by reference. 55 vasodilation may, in turn, provide better circulation and dis Empirical studies indicate that the Amino Acid Norvaline tribution of Citrulline in the body. Absorption may be inhibits the enzyme arginase and thus decreases the rate of improved since Amino Acid salts with inorganic acids are conversion of the Amino Acid Arginine to urea. Takeyori much more water soluble than single administration Amino Saheki, et al. “Regulation of Urea Synthesis in Rat Liver Acids. Additionally a much lesser dose may be required for available at http://b.oxfordjournals.org/cgi/content/abstract/ 60 vasodilation to take place, compared to the single adminis 86/3/745?ijkey=5d 134456b7443ca36c809269462276e tration of Citrulline or nitrates. Citrulline Nitrate is likewise 532549798&key type2=tf ipsecsha, the contents of which more water soluble than single administration Citrulline. are hereby incorporated by reference. Accordingly, Applicants have discovered that the Creatine An October 2004 Journal of Nutrition report indicates that compound according to the third implementation, when the Amino Acid Ornithine promotes anabolism and stimu 65 ingested, provides enhanced Nitric Oxide (NO ) production lates muscle protein synthesis. Michael J. Rennie, et al. while providing improved vasodilation effects over single “Branched-Chain Amino Acids as Fuels and Anabolic Sig administration of Creatine, the single administration of US 8,466,187 B2 19 20 Nitrates, or the single administration of Nitrites. Improved buffer and stored in stability chambers in screw capped vasodilation may, in turn, provide better circulation and dis bottles at 37° C. and 40° C., respectively. Samples were tribution of Creatine in the body. Absorption may be collected at predetermined time points and analyzed for cre improved since Amino Acid salts with inorganic acids are atine and degradation products ifany, using a validated HPLC much more water soluble than single administration Amino method. Changes in the pH, clarity and color of the samples Acids. Additionally a much lesser dose may be required for were also determined. The order of degradation and rate vasodilation to take place, compared to the single adminis constant were determined by graphical method. Results: The tration of nitrates. degradation rate constants (k) for CN, CM and BC at 37°C. Enhancing a molecule's solubility can enhance it’s bio in pH 2.5 buffer were 0.075+0.001, 0.119+0.011 and availability, rate of absorption by the GI tract, and as a result, 10 0.108+0.002 (day-1) while that at 40°C. in pH 6.8 buffer were its concentration in the muscle tissue and its effectiveness. 0.115+0.001, 0.015+0.001 and 0.013+0.002 (day-1), respec As we have established, the nitrate salts of creatine and other tively. The pH of CN samples at 40° C. in pH 6.8 buffer molecules are exceptionally more soluble that their counter changed from 2.83+0.01 to 4.31+0.01 within a period of 12 parts. Recent studies on creatine nitrate show 1100% days. The pH changes noticed at 37° C. in pH 2.5 buffer improved solubility over creatine monohydrate. 15 samples over the same period of time for CM, and BC were Study 1 3.08+0.01 to 4.12+0.01 and 3.11+0.01 and 4.16+0.01, respectively. No significant change in pH was observed for Intrinsic Dissolution Profiles of Creatine Nitrate, the rest of the samples. No change in the color and the clarity Creatine Monohydrate and Buffered Creatine was noticed over 12 days. Conclusions: All the creatine samples followed first order degradation kinetics under both Objective: The objective of this study was to determine the these experimental conditions. Thek value for CN was found dissolution characteristics of three different forms of com to be higher at 40°C. in pH 6.8 buffer as compared to at 37° mercially available creatine including creatine nitrate (CN), C. in pH 2.5 buffer. However, both CM and BC showed a creatine monohydrate (CM) and buffered creatine (BC) under faster rate of degradation at 37°C. in pH 2.5 buffer than at 40° different temperature and pH. Methods: Intrinsic dissolution 25 C. in pH 6.8 buffer. The major degradation product detected studies were carried out at 37°C. and room temperature in pH was creatinine. For CN the increase in pH was higher at 40°C. 2.5 and 7.4 buffer using modified Wood's apparatus. CN, CM in pH 6.8 buffer as compared to 37° C. in pH 2.5 buffer. and BC samples (-0.5 g) were compressed in the dies with However, opposite effect was noticed for both CM and BC. constant surface area of 1.21 cm2 using a Carver press at 2000 Study 3 psi with a dwell time of 10 sec. These dies were placed in the 30 USP dissolution apparatus (type II) containing 140 ml of Equilibrium Solubility Studies of Creatine Nitrate, dissolution media, with paddle speed of 50 rpm. Dissolution Creatine Monohydrate and Buffered Creatine medium were collected at definite time intervals over a period of 3 hours for CN and 7 hours for both CM and BC and Ambrish Panditl, Pinal Mistryl, Pat Dib2, Alexander analyzed for creatine using a validated HPLC method. 35 Nikolaidis3 Alekha K. Dashl Results: A plot of the amount of creatine dissolved (mg)/ Department of Pharmacy Sciences, Creighton University, Surface area (cm2) versus time gives the slope (k’) which is Omaha, Nebr. 68178. Department of Physiological Science directly proportional to the dissolution rate constant. The k" UCLA. Aristotle University Of Thessaloniki. (mg/cm2 hr) values for CN, CM and BC in pH 2.5 buffer at Objective: The objective of this study was to determine the room temperature were 293.0+3.48, 59.1+2.06 and 40 equilibrium solubility of creatine nitrate (CN), creatine 71.1+0.59. At 37° C. these k (mg/cm2 hr) values were monohydrate (CM) and buffered creatine (BC) in water at 327.3+2.66, 97.9+0.88 and 117.9+1.12, respectively. In pH room temperature as well as in pH 2.5 buffer at room tem 7.4 buffer, thek (mg/cm2hr) values for CN, CM and BC were perature and 37°C. Methods: Excess amount of sample was 278.9+14.6, 52.1+0.22 and 50.6+0.95 at room temperature added to the appropriate solvent and temperature was main and 319.5+14.3, 86.0+5.05 and 96.9-9.28 at 37° C., respec 45 tained and agitated at 150 rpm. The Supernatant was collected tively. Conclusions: The dissolution rates of all three creatine after centrifugation at 24, 48, 72 hours till equilibration and forms were higher at 37° C. as compared to at room tempera analyzed by a HPLC method. Equilibration was confirmed ture. CM and BC showed a higher dissolution rate at pH 2.5 when the solubility values of two consecutive time points than that at pH 7.4, irrespective oftemperature. However, the were identical. The pH of the solution was monitored and dissolution rate of CN was not affected by the pH of the 50 Differential scanning calorimetry (DSC) thermograms of the dissolution media. Comparison of the dissolution profiles for solid samples before solubility and of the lyophilized sample these three creatine forms clearly indicated that CN has the after solubility studies were compared. Results: The equilib higher intrinsic dissolution rate constant as compared to CM rium solubility of CN, CM and BC in water at room tempera and BC irrespective of temperature and pH of the dissolution ture was reached in 44 hours, and was 210.3+4.82 mg/ml, media. Results of this study further predicta better bioavail 55 19.1+0.40 mg/ml and 19.2+0.55 mg/ml, respectively. How ability of CN as compared to CM and BC. ever, solubility for CN, CM and BC in pH 2.5 buffer at room Study 2 temperature was 208.2+6.01 mg/ml, 23.8+0.33 mg/ml and 21.2+0.09 mg/ml and achieved within 72 hours for CN and in Chemical Stability of Creatine Nitrate, Creatine 48 hours for CM and BC samples, respectively. At 37°C. and Monohydrate and Buffered Creatine in Solution 60 in pH 2.5 buffer, the equilibrium solubility was reached within 24 hours for all samples and was 325.9-6.10, Objective: The objective of this study was to determine the 31.5+0.71 and 32.6+0.67 for CN, CM, and BC. The pH of chemical stability of creatine nitrate (CN), creatine monohy solutions of CN, CM and BC in water at room temperature drate (CM) and buffered creatine (BC) under two different was 0.44+0.04, 8.24+0.14 and 10.03+0.02 respectively. storage conditions (37°C. in pH 2.5 buffer and 40°C. in pH 65 However, these values in pH 2.5 buffer at room temperature 6.8 buffer). Methods: A known concentration (~10 mg/ml) of were 1.31+0.02, 3.44+0.02 and 3.68+0.01 and at 37° C. this CN, CM and BC were prepared in both pH 2.5 and pH 6.8 was 1.13+0.07, 3.86+0.47 and 4.42+0.05, respectively. DSC US 8,466,187 B2 21 22 thermograms of the original samples and lyophilized samples oxidized, nitric oxide is recycled back into nitrate, which then were identical. Conclusions: The solubility of creatine nitrate has the potential to convert into nitric oxide once again. And was around 10 fold higher than that of CM or BC under these the cycle continues to repeat itself. This creates an exciting experimental conditions studied, where as no significant dif alternative to nitric oxide production, and carries profound ference in the solubility of CM and BC were noticed. There implications for the bodybuilding community. was an increase in solubility of each of the creatine forms in A critical problem with nitric oxide is the short lifespan it pH 2.5 at a higher temperature. DSC analysis confirmed that has in the body. In just a few seconds, the nitric oxide mol no phase change was noticed during these solubility studies. ecule can be metabolized, and the athlete loses any benefit The effectiveness of creatine for increasing athletic perfor he/she may have received. A pump however must be sus mance and improving body composition and muscle anabo 10 lism and performance is very well established. Such is also tained for several minutes, if not hours, in order to result in the case for BCAAS (leucine, isoleucine, and valine), taurine those biochemical conditions required to stimulate muscle and carnitine. It is also well established that for these mol hypertrophy. And nitrates are capable of elevating nitric oxide ecules to have these effects, like all drugs, they must reach the production for up to 8 hours. site of action, i.e. the muscle. 15 Thus the use of nitrates represents an important alternative Creatine Nitrate & the Athlete to the classical L-arginine-NO-synthase pathway (2) So com Creatine Nitrate excels beyond its superior solubility, sta monly attempted in various sports Supplement formulations. bility, and dissolution. That’s because Creatine Nitrate over The efficacy of nitrates in athletic performance is over comes two primary drawbacks of creatine monohydrate. whelming in the clinical research. Nitrate consumption sig First, creatine monohydrate results in extreme intra and extra nificantly enhances nitric oxide production, resulting in cellular water and sodium retention. The intracellular water vasodilation, improved nutrient absorption, increased athletic retention is favorable. Cosmetically speaking however, the performance (3), and improved energetic function in working extracellular water retention is an unfavorable effect, as an muscles during exercise (12). For example, during low and athlete's muscles develop a smooth, soft, and bloated appear moderate intensity exercise by humans, Supplementation ance. Second and most importantly, the extreme extracellular 25 with nitrates has been reported to reduce the amount of oxy water retention may restrict muscle growth. Functionally gen required. During high intensity athletic exercise, nitrate speaking, the extracellular water retention may push back Supplementation enhances tolerance to high intensity train against muscle cells that are attempting to expand in size. ing, effectively extending the “time to exhaustion'(4). Creatine Nitrate expels excess extracellular water and Organic nitrates also function as permeation enhancers. Sodium retention, while simultaneously hydrating and Super 30 This is beneficial because enhanced permeation increases saturating muscle cells with creatine. This offers a HUGE intestinal absorption of all nutrients coingested. This may benefit to athletes, encouraging muscle cells to expand in size allow for a superior quantity of anabolic nutrients to be without resistance from extracellular fluid. In addition, ath absorbed and taken up into muscle cells, assisting athletes letes using Creatine Nitrate may achieve a leaner, drier, and with the growth and repair of muscle tissue. Nitrates are even harder look to their muscle tissue; a stark contrast to the puffy 35 able to allow absorption of large macromolecules Such as and bloated look created by creatine monohydrate. Creatine insulin (5,6,7). Nitrate however is more than “Creatine Nitrate, as the nitrate For decades, the pharmaceutical industry has used nitrates component offers tremendous functional advantages to ath to induce direct and rapid vasodilation. And today, clinical letes. research is proving that nitrates may produce beneficial Nitrates provide substantial benefits to athletes and body 40 effects on blood pressure and cardiovascular health (8). In builders, as supported by clinical research. Nitrates are fact, a recent clinical study investigated the effects of 5 times organic anions naturally occurring in the human , with the amount of nitrates (1,316 mg per day for a 70 kg adult) close to 80% of dietary nitrates found in vegetables. Fruits currently recommended by the World Health Organization and processed meats represent additional sources of nitrates (259 mg per day for a 70 kg adult) and showed no adverse in the human diet. In fact, researchers at Michigan State 45 health or safety effects. The study results revealed an average University have suggested nitrates may be nutritious (13). So reduction in diastolic blood pressure by 4.5 mmHg. Effects on what benefit does supplementation with nitrates offer to ath systolic blood pressure were not observed (14.15). letes? Nitrates themselves offer many benefits to athletes. Com Today, nitric oxide and pre-workout nitric oxide perfor bined with the clinical research behind creatine supporting mance enhancing formulas have grown in popularity. Nitric 50 creatine's positive benefits to athletes, Creatine Nitrate is the oxide formulas are used to increase muscular “pumps.” first creatine to solve to the solubility, stability, and dissolu vasodilation, and nutrient transport to the muscle to assist in tion challenges while simultaneously providing up to 8 hours greater aerobic performance and recovery. However, most of powerful vasodilation that workout enthusiasts demand formulas utilize the amino acid L-arginine, a precursor to References nitric oxide, as their base. Recently, L-arginine has been 55 The following references are hereby incorporated herein proven to be ineffective for elevating nitric oxide levels. by reference. L-arginine has also been proven ineffective at enhancing ath 1. Glucose-and arginine-induced insulin secretion by letic performance (9,10,11). Yet L-arginine is present in human pancreatic 13-cells: the role of HERG K+ channels in nearly every single nitric oxide formula on the market. Con firing and release trary to popular belief, most of the “pump' feeling experi 60 2. Does NO metabolism play a role in the effects of veg enced by trainees is derived from an insulin increase follow etables in health?Nitric oxide formation via the reduction of ing L-arginine Supplementation (1). nitrites and nitrates. Dina Ralt * Gertner Institute for Epide As recent clinical research confirms, the reduction of inor miology and Health Policy Research, Tel Hashomer, Israel ganic nitrate (NO3-) and nitrite (NO2-) in vivo results in nitric 3. Larsen F J. Weitzberg E. Lundberg JO. Ekblom B. oxide production. Not only does nitrate generate nitric oxide, 65 Effects of dietary nitrate on oxygen cost during exercise. Acta but nitrate and nitrite are inert end-products of nitric oxide Physiol (Oxf). 2007 September 191(1):59-66. Epub 2007 oxidation. That is, nitrate converts into nitric oxide, and once Jul. 17. US 8,466,187 B2 23 24 4. Stephen J. Bailey, 1 Paul Winyard.2 Anni Vanhatalo, 1 Accordingly, Applicants have discovered that the Leucine Jamie R. Blackwell, 1 Fred J. DiMenna, 1 Daryl P. Wilker compound according to the fifth implementation, when son, 1 Joanna Tarr.2 Nigel Benjamin.2 and Andrew M. ingested, provides enhanced Nitric Oxide (NO ) production Jones 1. Dietary nitrate supplementation reduces the O2 cost while providing improved vasodilation effects over single of low-intensity exercise and enhances tolerance to high administration of Leucine, the single administration of intensity exercise in humans. 1School of Sport and Health Nitrates, or the single administration of Nitrites. Improved Sciences and; 2Peninsula College of Medicine and Dentistry, vasodilation may, in turn, provide better circulation and dis University of Exeter, Exeter, United Kingdom tribution of Leucine in the body. Absorption may be improved 5. Fetih G, Habib F, Katsumi H, OkadaN, Fujita T. Attia M, since Amino Acid salts with inorganic acids are much more 10 water Soluble than single administration Amino Acids. Addi Yamamoto A. Excellent absorption enhancing characteristics tionally a much lesser dose may be required for vasodilation of NO donors for improving the intestinal absorption of to take place, compared to the single administration of poorly absorbable compound compared with conventional nitrates. Leucine Nitrate is likewise more water soluble than absorption enhancers. single administration Leucine. 6. Koichi Takahashia, , Nanako Numataa, Natsumi 15 Accordingly, Applicants have discovered that the Norval Kinoshitaa, Naoki Utoguchib, Tadanori Mayumic, Nobuyasu ine compound according to the sixth implementation, when Mizunoa. Characterization of the influence of nitric oxide ingested, promotes vasodilation through the inhibition of donors on intestinal absorption of macromolecules. Interna arginase, while promoting Nitric Oxide formation via the tional Journal of Pharmaceutics 286 (2004) 89-97 nitrate mechanism. Improved vasodilation may, in turn, pro 7. Fetih G, Habib F, Okada N, Fujita T. Attia M. Yamamoto vide better circulation and distribution of Norvaline in the A. Nitric oxide donors can enhance the intestinal transport body. Absorption may be improved since Amino Acid salts and absorption of insulin and ASu(1.7)-eel calcitonin in rats. with inorganic acids are much more water soluble than single 8. Supatra Porasuphatanaa, Pei Tsaib, Gerald M. Rosenb. administration Amino Acids. Additionally a much lesser dose The generation of free radicals by nitric oxide synthase. Com may be required for vasodilation to take place, compared to parative and Physiology Part C 134 (2003) 25 the single administration of nitrates. Norvaline Nitrate may 281-289 1532-0456/03/S see front matter 2002 Elsevier likewise be more water soluble than single administration Science Inc. All rights reserved. PII: S1 532-0456702.00271 Norvaline. 5 Review. Accordingly, Applicants have discovered that the Orni 9. Olek RA et al. A single oral intake of arginine does not thine compound according to the seventh implementation, affect performance during repeated Wingate anaerobic test. J 30 when ingested, provides an additional vasodilation mecha Sports Med Phys Fitness. 2010 March: 50(1):52-6. nism, reducing the amount of Ornithine needed and the 10. Liu T H. Wu C L, Chiang CW, Lo Y W, Tseng HF, amount of time needed for the vasodilating properties to Chang CK. No effect of shortterm arginine supplementation manifest. Improved vasodilation may, in turn, provide better on nitric oxide production, metabolism and performance in circulation and distribution of Ornithine in the body. Absorp intermittent exercise in athletes. J Nutr Biochem. 2008 Aug. 35 tion may be improved since Amino Acid salts with inorganic 15. Epub ahead of print acids are much more water Soluble than single administration 11. Bescos R. Gonzalez-Haro C. Pujol P. Drobnic F. Amino Acids. Applicants have also discovered that Ornithine Alonso E. Santolaria ML, Ruiz, O. Esteve M, Galilea P. Nitrate begins acting as fast as any other nitrate, since the Effects of dietary L-arginine intake on cardiorespiratory and NO-group of the salt requires minimal conversion to yield metabolic adaptation in athletes. Int J Sport Nutr Exerc 40 Nitric Oxide. Additionally, a much lesser dose may be Metab. 2009 August: 19(4):355-65. required for vasodilation to take place, compared to the single 12. Larsen F J. Weitzberg E. Lundberg JO. Ekblom B. administration of nitrates. Ornithine Nitrate may likewise be Dietary nitrate reduces maximal oxygen consumption while more water soluble than single administration Ornithine. maintaining work performance in maximal exercise. Free Accordingly, Applicants have discovered that the Histidine Radic Biol Med. 2010 Jan. 15:48(2):342-7. Epub 2009 Nov. 45 compound according to the eighth implementation, when 12. ingested, provides a vasodilation mechanism. Vasodilation 13. American Journal of Clinical Nutrition, doi:10.3945/ may, in turn, provide better circulation and distribution of ajcn2008.27 131 Histidine in the body. Applicants have likewise discovered 14. Tanja Sobko, Claude Marcus, Mirco Govoni, Shigeru that the Histidine compound according to the ninth imple Kamiya. “Dietary nitrate in Japanese traditional foods lowers 50 mentation, when ingested, promotes carnosine production, diastolic blood pressure in healthy volunteers. Nitric Oxide thus increasing muscle power, endurance and recuperation. Volume 22, Issue 2, Pages 136-140 Absorption may be improved since Amino Acid salts with 15. http://www.foodnavigator.com/Product-Categories/ inorganic acids are much more water Soluble than single Preservativesand-acidulants/Dietary-nitrates-maybe-benefi administration Amino Acids. Applicants have also discovered cial-for-heart-health-Study/?utm_source=Newsletter 55 that Histidine Nitrate begins acting as fast as any other nitrate, Product&utm medium email&utm_campaign=Newsletter since the NO-group of the salt requires minimal conver %2BProduct sion to yield Nitric Oxide. Additionally, a much lesser dose Accordingly, Applicants have discovered that the may be required for vasodilation to take place, compared to Glutamine compound according to the fourth implementa the single administration of nitrates. Histidine Nitrate may tion, when ingested, counters the Nitric Oxide (NO ) inhib 60 likewise be more water soluble than single administration iting characteristics of Glutamine. Absorption of Glutamine Histidine. may be improved since Amino Acid salts with inorganic acids Accordingly, Applicants have discovered that the Beta Ala are much more water Soluble than single administration nine compound according to the ninth implementation, when Amino Acids. Additionally a much lesser dose may be ingested, provides vasodilation. Vasodilation may, in turn, required for vasodilation to take place, compared to the single 65 provide better circulation and distribution of Beta Alanine in administration of nitrates. Glutamine Nitrate may likewise be the body. Applicants have likewise discovered that the Beta more water soluble than single administration Glutamine. Alanine compound according to the tenth implementation, US 8,466,187 B2 25 26 when ingested, promotes carnosine production, thus increas following references which are hereby incorporated herein by ing muscle power, endurance and recuperation. Absorption reference—Bailey, Stephen G. et al., “Dietary nitrate supple may be improved since Amino Acid salts with inorganic acids mentation reduces the O2 cost of low-intensity exercise and are much more water Soluble than single administration enhances tolerance to high-intensity exercise in humans'. Amino Acids. Applicants have also discovered that Beta Ala Press. J Appl Physiol (Aug. 6, 2009) and Bailey, Stephen G. nine Nitrate begins acting as fast as any other nitrate, since the et al., “Dietary nitrate Supplementation enhances muscle con NO-group of the salt requires minimal conversion to yield tractile efficiency during knee-extensor exercise in humans'. Nitric Oxide. Additionally, a much lesser dose may be JAppl Physiol 109:135-148, 2010). required for vasodilation to take place, compared to the single In these same references it is also very well described administration of nitrates. Beta Alanine Nitrate may likewise 10 nitrate's positive effect on athletic endurance and muscle be more water soluble than single administration Beta Ala strength. Oxygen is needed by the body to produce energy nine. which by itself is needed for all the metabolic processes in the Accordingly, Applicants have discovered that the Agma body, including those that Compositions of the present dis tine compound according to the eighth implementation, when closure are involved in. Thus co-administration of nitrate ion ingested, counteracts the Nitric Oxide inhibiting effect of 15 with Compositions of the present disclosure furthermore single administration Agmatine. Absorption may be increases their distribution to the muscle and their effective improved since Amino Acid salts with inorganic acids are CSS. much more water soluble than single administration Amino Therefore, not only does the binding of nitrate salt with Acids. Applicants have also discovered that Agmatine Nitrate Compounds improve their bioavalability, absorption and begins acting as fast as any other nitrate, since the NO effectiveness, but also the co-administration of nitrate group of the salt requires minimal conversion to yield Nitric through another nitrate salt, acid or a natural source of nitrate Oxide. Agmatine Nitrate may likewise be more water soluble in a Composition of the present disclosure shall have similar than single administration Agmatine. effects, albeit lower than in the case of nitrate bonded with the Accordingly, Applicants have discovered that not only do molecule. the foregoing amino acid nitrate or nitrite compounds provide 25 Via all the above mechanisms, concomitant nitrate or the effects discussed above, but that Amino Acid Composi nitrite administrationina composition with an amino acid can tions (amino acids mixed with independent sources of nitrates Substantially increase the concentration of an amino acid in and/or nitrites) enhance bioavailability, absorption, vasodila the target muscles (e.g., cells for the congitive tion, water solubility, distribution to muscles, and the like of enhancement properties of phenylalanine.carnitine, glycine, certain Amino Acids, as well as prevent Nitrate tolerance and 30 and tyrosine, and Muscle cells for the performance enhancing counter Nitric Oxide inhibiting effects of certain Amino properties of Agmatine Arginine, Beta Alanine, Citrulline, Acids. Creatine, Glutamine, L-Histidine, Isoleucine, Leucine, Nor As demonstrated by Anjali Pradhan and Juan Vera, “Effect valine, Ornithine and Taurine). In the case of Creatine, this is of Anions on the Solubility of Zwitterionic AInino Acids”. further enhanced by the nitrate’s ability to preserve muscle Journal of Chemical and Engineering data, Vol 45, 140-143 35 Creatine loads. (2000) (which is hereby incorporated herein by reference), Therefore, concomitant nitrate or nitrite administration in a the co-existence of the nitrate ion can enhance the solubility composition with an amino acid (just as with amino acid of various amino acids by 300-400%. Although the change in nitrate or nitrite compounds discussed previously) can solubility is significantly lower than that of the case of a salt improvemental focus, cognitive function, athletic and muscle with a nitrate, it is enough to make a difference in absorption 40 performance, endurance, and strength, and produces much in-vivo. greater synergistic results than the use of only an amino acid Furthermore, the nitrate ion enhances absorption of com alone or a nitrate and a nitrite alone. pounds by the intestine. Nitrates increase bioavailability by: The invention claimed is: increasing intestinal absorption of nutrients; and increasing 1. A method for increasing athletic performance in a human vasodilation and blood flow and blood is the carrier of the 45 oranimal, the method comprising administering to the human nutrients to cells. See for example, the following references or animal a pharmaceutically effective amount of an amino which are hereby incorporated herein by reference: Takahashi acid composition comprising at least one constituent selected K et al. “Characterization of the influence of nitric oxide from the group consisting of a nitrate, a nitrite, and both, and donors on intestinal absorption of macromolecules.” Int J Arginine. Pharm 2004; 286:89-97; Fetih G. et al. “Nitric oxide donors 50 2. A method for increasing distribution of Amino Acids to can enhance the intestinal transport and absorption of insulin muscles in a human or animal, the method comprising admin and Asu(1.7)-eel calcitonin in rats. J Control Release 2005; istering to the human or animal a pharmaceutically effective 106:287-97; Fetih G. et al. “Excellent absorption enhancing amount of an amino acid composition comprising at least one characteristics of NO donors for improving the intestinal constituent selected from the group consisting of a nitrate, a absorption of poorly absorbable compound compared with 55 nitrite, and both, and Arginine. conventional absorption enhancers. Drug Metab Pharma 3. A method for increasing solubility of Amino Acids in a cokinet 2006; 21:222-9; and Mitchell, G. E., Little, C.O., Jr. human or animal, the method comprising administering to the & Greathouse, T. R. (1964). “Influence of nitrate and nitrite, human or animal a pharmaceutically effective amount of an on carotene disappearance from the rat intestine. Life Sci. 4. amino acid composition comprising at least one constituent 385. 60 selected from the group consisting of a nitrate, a nitrite, and Also, the nitrate ion can cause vasodilatation after reduc both, and Arginine. tion to nitrite and then nitric oxide, improve blood circulation, 4. A method for increasing athletic performance in a human to the muscles and thus distribution of these compounds to the oranimal, the method comprising administering to the human muscle, as well as oxygen distribution to the muscles. Muscle or animal a pharmaceutically effective amount of an amino oxygen is needed to provide energy which is needed for all 65 acid composition comprising at least one constituent selected muscle anabolic actions to take place as well as for the active from the group consisting of a nitrate, a nitrite, and both, and transport of above nutrients via the cell membrane. See the Agmatine. US 8,466,187 B2 27 28 5. A method for increasing athletic performance in a human 16. A method for increasing athletic performance in a oranimal, the method comprising administering to the human human or animal, the method comprising administering to the or animal a pharmaceutically effective amount of an amino human or animal a pharmaceutically effective amount of an acid composition comprising at least one constituent selected amino acid composition comprising at least one constituent from the group consisting of a nitrate, a nitrite, and both, and selected from the group consisting of a nitrate, a nitrite, and Beta Alanine. both, and Cysteine. 6. A method for increasing athletic performance in a human 17. A method for increasing athletic performance in a oranimal, the method comprising administering to the human human or animal, the method comprising administering to the or animal a pharmaceutically effective amount of an amino human or animal a pharmaceutically effective amount of an acid composition comprising at least one constituent selected 10 amino acid composition comprising at least one constituent from the group consisting of a nitrate, a nitrite, and both, and selected from the group consisting of a nitrate, a nitrite, and Citrulline. both, and Glycine. 7. A method for increasing athletic performance in a human 18. A method for increasing athletic performance in a oranimal, the method comprising administering to the human 15 human or animal, the method comprising administering to the or animal a pharmaceutically effective amount of an amino human or animal a pharmaceutically effective amount of an acid composition comprising at least one constituent selected amino acid composition comprising at least one constituent from the group consisting of a nitrate, a nitrite, and both, and selected from the group consisting of a nitrate, a nitrite, and Creatine. both, and Lysine. 8. A method for increasing athletic performance in a human 19. A method for increasing athletic performance in a oranimal, the method comprising administering to the human human or animal, the method comprising administering to the or animal a pharmaceutically effective amount of an amino human or animal a pharmaceutically effective amount of an acid composition comprising at least one constituent selected amino acid composition comprising at least one constituent from the group consisting of a nitrate, a nitrite, and both, and selected from the group consisting of a nitrate, a nitrite, and Glutamine. 25 both, and Methionine. 9. A method for increasing athletic performance in a human 20. A method for increasing athletic performance in a oranimal, the method comprising administering to the human human or animal, the method comprising administering to the or animal a pharmaceutically effective amount of an amino human or animal a pharmaceutically effective amount of an acid composition comprising at least one constituent selected amino acid composition comprising at least one constituent from the group consisting of a nitrate, a nitrite, and both, and 30 selected from the group consisting of a nitrate, a nitrite, and L-Histidine. both, and Proline. 10. A method for increasing athletic performance in a 21. A method for increasing athletic performance in a human oranimal, the method comprising administering to the human or animal, the method comprising administering to the human or animal a pharmaceutically effective amount of an human or animal a pharmaceutically effective amount of an amino acid composition comprising at least one constituent 35 amino acid composition comprising at least one constituent selected from the group consisting of a nitrate, a nitrite, and selected from the group consisting of a nitrate, a nitrite, and both, and Isoleucine. both, and Tyrosine. 11. A method for increasing athletic performance in a 22. A method for increasing athletic performance in a human oranimal, the method comprising administering to the human or animal, the method comprising administering to the human or animal a pharmaceutically effective amount of an 40 human or animal a pharmaceutically effective amount of an amino acid composition comprising at least one constituent amino acid composition comprising at least one constituent selected from the group consisting of a nitrate, a nitrite, and selected from the group consisting of a nitrate, a nitrite, and both, and Leucine. both, and Phenylalanine. 12. A method for increasing athletic performance in a 23. A method for increasing distribution of Amino Acids to human oranimal, the method comprising administering to the 45 muscles in a human or animal, the method comprising admin human or animal a pharmaceutically effective amount of an istering to the human or animal a pharmaceutically effective amino acid composition comprising at least one constituent amount of an amino acid composition comprising at least one selected from the group consisting of a nitrate, a nitrite, and constituent selected from the group consisting of a nitrate, a both, and Norvaline. nitrite, and both, and Agmatine. 13. A method for increasing athletic performance in a 50 24. A method for increasing distribution of Amino Acids to human oranimal, the method comprising administering to the muscles in a human or animal, the method comprising admin human or animal a pharmaceutically effective amount of an istering to the human or animal a pharmaceutically effective amino acid composition comprising at least one constituent amount of an amino acid composition comprising at least one selected from the group consisting of a nitrate, a nitrite, and constituent selected from the group consisting of a nitrate, a both, and Ornithine. 55 nitrite, and both, and Beta Alanine. 14. A method for increasing athletic performance in a 25. A method for increasing distribution of Amino Acids to human oranimal, the method comprising administering to the muscles in a human or animal, the method comprising admin human or animal a pharmaceutically effective amount of an istering to the human or animal a pharmaceutically effective amino acid composition comprising at least one constituent amount of an amino acid composition comprising at least one selected from the group consisting of a nitrate, a nitrite, and 60 constituent selected from the group consisting of a nitrate, a both, and Valine. nitrite, and both, and Citrulline. 15. A method for increasing athletic performance in a 26. A method for increasing distribution of Amino Acids to human oranimal, the method comprising administering to the muscles in a human or animal, the method comprising admin human or animal a pharmaceutically effective amount of an istering to the human or animal a pharmaceutically effective amino acid composition comprising at least one constituent 65 amount of an amino acid composition comprising at least one selected from the group consisting of a nitrate, a nitrite, and constituent selected from the group consisting of a nitrate, a both, and Aspartic Acid. nitrite, and both, and Creatine. US 8,466,187 B2 29 30 27. A method for increasing distribution of Amino Acids to 38. A method for increasing distribution of Amino Acids to muscles in a human oranimal, the method comprising admin muscles in a human or animal, the method comprising admin istering to the human or animal a pharmaceutically effective istering to the human or animal a pharmaceutically effective amount of an amino acid composition comprising at least one amount of an amino acid composition comprising at least one constituent selected from the group consisting of a nitrate, a constituent selected from the group consisting of a nitrate, a nitrite, and both, and Glutamine. nitrite, and both, and Methionine. 28. A method for increasing distribution of Amino Acids to 39. A method for increasing distribution of Amino Acids to muscles in a human oranimal, the method comprising admin muscles in a human or animal, the method comprising admin istering to the human or animal a pharmaceutically effective istering to the human or animal a pharmaceutically effective amount of an amino acid composition comprising at least one 10 amount of an amino acid composition comprising at least one constituent selected from the group consisting of a nitrate, a constituent selected from the group consisting of a nitrate, a nitrite, and both, and L-Histidine. nitrite, and both, and Proline. 29. A method for increasing distribution of Amino Acids to 40. A method for increasing distribution of Amino Acids to muscles in a human oranimal, the method comprising admin 15 muscles in a human or animal, the method comprising admin istering to the human or animal a pharmaceutically effective istering to the human or animal a pharmaceutically effective amount of an amino acid composition comprising at least one amount of an amino acid composition comprising at least one constituent selected from the group consisting of a nitrate, a constituent selected from the group consisting of a nitrate, a nitrite, and both, and Isoleucine. nitrite, and both, and Tyrosine. 30. A method for increasing distribution of Amino Acids to 41. A method for increasing distribution of Amino Acids to muscles in a human oranimal, the method comprising admin muscles in a human or animal, the method comprising admin istering to the human or animal a pharmaceutically effective istering to the human or animal a pharmaceutically effective amount of an amino acid composition comprising at least one amount of an amino acid composition comprising at least one constituent selected from the group consisting of a nitrate, a constituent selected from the group consisting of a nitrate, a nitrite, and both, and Leucine. 25 nitrite, and both, and Phenylalanine. 31. A method for increasing distribution of Amino Acids to 42. A method for increasing solubility of Amino Acids in a muscles in a human oranimal, the method comprising admin human or animal, the method comprising administering to the istering to the human or animal a pharmaceutically effective human or animal a pharmaceutically effective amount of an amount of an amino acid composition comprising at least one amino acid composition comprising at least one constituent constituent selected from the group consisting of a nitrate, a 30 selected from the group consisting of a nitrate, a nitrite, and nitrite, and both, and Norvaline. both, and Agmatine. 32. A method for increasing distribution of Amino Acids to 43. A method for increasing solubility of Amino Acids in a muscles in a human oranimal, the method comprising admin human or animal, the method comprising administering to the istering to the human or animal a pharmaceutically effective human or animal a pharmaceutically effective amount of an amount of an amino acid composition comprising at least one 35 amino acid composition comprising at least one constituent constituent selected from the group consisting of a nitrate, a selected from the group consisting of a nitrate, a nitrite, and nitrite, and both, and Ornithine. both, and Beta Alanine. 33. A method for increasing distribution of Amino Acids to 44. A method for increasing solubility of Amino Acids in a muscles in a human oranimal, the method comprising admin human or animal, the method comprising administering to the istering to the human or animal a pharmaceutically effective 40 human or animal a pharmaceutically effective amount of an amount of an amino acid composition comprising at least one amino acid composition comprising at least one constituent constituent selected from the group consisting of a nitrate, a selected from the group consisting of a nitrate, a nitrite, and nitrite, and both, and Valine. both, and Citrulline. 34. A method for increasing distribution of Amino Acids to 45. A method for increasing solubility of Amino Acids in a muscles in a human oranimal, the method comprising admin 45 human or animal, the method comprising administering to the istering to the human or animal a pharmaceutically effective human or animal a pharmaceutically effective amount of an amount of an amino acid composition comprising at least one amino acid composition comprising at least one constituent constituent selected from the group consisting of a nitrate, a selected from the group consisting of a nitrate, a nitrite, and nitrite, and both, and Aspartic Acid. both, and Creatine. 35. A method for increasing distribution of Amino Acids to 50 46. A method for increasing solubility of Amino Acids in a muscles in a human oranimal, the method comprising admin human or animal, the method comprising administering to the istering to the human or animal a pharmaceutically effective human or animal a pharmaceutically effective amount of an amount of an amino acid composition comprising at least one amino acid composition comprising at least one constituent constituent selected from the group consisting of a nitrate, a selected from the group consisting of a nitrate, a nitrite, and nitrite, and both, and Cysteine. 55 both, and Glutamine. 36. A method for increasing distribution of Amino Acids to 47. A method for increasing solubility of Amino Acids in a muscles in a human oranimal, the method comprising admin human or animal, the method comprising administering to the istering to the human or animal a pharmaceutically effective human or animal a pharmaceutically effective amount of an amount of an amino acid composition comprising at least one amino acid composition comprising at least one constituent constituent selected from the group consisting of a nitrate, a 60 selected from the group consisting of a nitrate, a nitrite, and nitrite, and both, and Glycine. both, and L-Histidine. 37. A method for increasing distribution of Amino Acids to 48. A method for increasing solubility of Amino Acids in a muscles in a human oranimal, the method comprising admin human or animal, the method comprising administering to the istering to the human or animal a pharmaceutically effective human or animal a pharmaceutically effective amount of an amount of an amino acid composition comprising at least one 65 amino acid composition comprising at least one constituent constituent selected from the group consisting of a nitrate, a selected from the group consisting of a nitrate, a nitrite, and nitrite, and both, and Lysine. both, and Isoleucine. US 8,466,187 B2 31 32 49. A method for increasing solubility of Amino Acids in a 55. A method for increasing solubility of Amino Acids in a human oranimal, the method comprising administering to the human or animal, the method comprising administering to the human or animal a pharmaceutically effective amount of an human or animal a pharmaceutically effective amount of an amino acid composition comprising at least one constituent amino acid composition comprising at least one constituent selected from the group consisting of a nitrate, a nitrite, and selected from the group consisting of a nitrate, a nitrite, and both, and Glycine. both, and Leucine. 56. A method for increasing solubility of Amino Acids in a 50. A method for increasing solubility of Amino Acids in a human or animal, the method comprising administering to the human oranimal, the method comprising administering to the human or animal a pharmaceutically effective amount of an human or animal a pharmaceutically effective amount of an amino acid composition comprising at least one constituent amino acid composition comprising at least one constituent 10 selected from the group consisting of a nitrate, a nitrite, and selected from the group consisting of a nitrate, a nitrite, and both, and Lysine. both, and Norvaline. 57. A method for increasing solubility of Amino Acids in a 51. A method for increasing solubility of Amino Acids in a human or animal, the method comprising administering to the human or animal a pharmaceutically effective amount of an human oranimal, the method comprising administering to the 15 human or animal a pharmaceutically effective amount of an amino acid composition comprising at least one constituent amino acid composition comprising at least one constituent selected from the group consisting of a nitrate, a nitrite, and selected from the group consisting of a nitrate, a nitrite, and both, and Methionine. both, and Ornithine. 58. A method for increasing solubility of Amino Acids in a 52. A method for increasing solubility of Amino Acids in a human or animal, the method comprising administering to the human oranimal, the method comprising administering to the human or animal a pharmaceutically effective amount of an human or animal a pharmaceutically effective amount of an amino acid composition comprising at least one constituent amino acid composition comprising at least one constituent selected from the group consisting of a nitrate, a nitrite, and both, and Proline. selected from the group consisting of a nitrate, a nitrite, and 59. A method for increasing solubility of Amino Acids in a both, and Valine. 25 human or animal, the method comprising administering to the 53. A method for increasing solubility of Amino Acids in a human or animal a pharmaceutically effective amount of an human oranimal, the method comprising administering to the amino acid composition comprising at least one constituent human or animal a pharmaceutically effective amount of an selected from the group consisting of a nitrate, a nitrite, and amino acid composition comprising at least one constituent both, and Tyrosine. selected from the group consisting of a nitrate, a nitrite, and 30 60. A method for increasing solubility of Amino Acids in a both, and Aspartic Acid. human or animal, the method comprising administering to the 54. A method for increasing solubility of Amino Acids in a human or animal a pharmaceutically effective amount of an human oranimal, the method comprising administering to the amino acid composition comprising at least one constituent human or animal a pharmaceutically effective amount of an selected from the group consisting of a nitrate, a nitrite, and amino acid composition comprising at least one constituent 35 selected from the group consisting of a nitrate, a nitrite, and both, and Phenylalanine. both, and Cysteine. k k k k k

Top View