USOO856.9369B2

(12) United States Patent (10) Patent No.: US 8,569,369 B2 Kramer et al. (45) Date of Patent: *Oct. 29, 2013

(54) AMINO ACID COMPOUNDS OTHER PUBLICATIONS (75) Inventors: Ronald Kramer, Phoenix, AZ (US); Jablecka et al., MedSci Monit 10(I):CR29-32 (2004). Alexander Nikolaidis, New Kallikratia Maynard et al., J. Nutr. 131:287-290 (2001). (GR) Ruel et al., J. Thorac Cardiovasc. Surg 135:762-77, 2008. Rytlewski et al., European Journal of Obstetrics & Gynecology and (73) Assignee: Thermolife International, LLC, Reproductive Biology 138:23-28 (2008). Phoenix, AZ (US) Schwedheim et al., Br J Clin Pharmacol 65(1):51-59 (2007). Smith et al., J. Thorac Cardiovasc. Surg 132:58-65 (2006). (*) Notice: Subject to any disclaimer, the term of this Rytlewski et al., Eur J. Clin Invest 35 (1):32-37 (2005). patent is extended or adjusted under 35 Ming et al., Circulation 110:3708-3714 (2004). U.S.C. 154(b) by 0 days. Romero et al., Cardiovascular Drug Reviews 24(3-4):275-290 (2006). This patent is Subject to a terminal dis Oka et al., Vasc Med 10:265-274 (2005). claimer. Hayashi et al., PNAS 102(38): 13681-13686 (2005). Grasemann et al., Eur Respir J 25:62-68 (2005). (21) Appl. No.: 13/468,231 Boger, J. Nutr 137:1650S-1655S (2007). Beghetti et al., J. Thorac Cardiovasc. Surg 132(6): 1501-1502 (2006). (22) Filed: May 10, 2012 Larsen et al., B. Acta Physiol 191(1):59-66 (2007). Berge, Journal of Pharmaceutical Sciences, Jan. 1977, vol. 66, No. 1. (65) Prior Publication Data Takahashi et al., “Characterization of the influence of nitric oxide donors on intestinal absorption of macromolecules.” International US 2012/O220643 A1 Aug. 30, 2012 Journal of Pharmaceutics vol. 286:89-97 (2004). Fetih et al., "Nitric oxide donors can enhance the intestinal transport and absorption of insulin and Asu 1.7-eel calcitonin in rats.” Journal Related U.S. Application Data of Controlled Release vol. 106:287-297 (2005). Fetih et al., “Excellent Absorption Enhancing Characteristics of NO (63) Continuation-in-part of application No. 12/946,153, Donors for Improving the Intestinal Absorption of Poorly Absorbable filed on Nov. 15, 2010, now Pat. No. 8,178,572, which Compound Compared with Conventional Absorption Enhancers.” Drug Metab. Pharmacokinet, vol. 21(3):222-229 (2006). is a continuation of application No. 12/336,938, filed Aniya et al., “Evaluation of Nitric Oxide Formation from Nitrates in on Dec. 17, 2008, now Pat. No. 8,034,836, which is a Pig Coronary Arteries,” Jpn. J. Pharmacal. vol. 71: 101-107 (1996). continuation of application No. 11/950,273, filed on T.F. Luscher, "Endogenous and exogenous nitrates and their role in Dec. 4, 2007, now Pat. No. 7,777,074. myocardial ischaemia.” Br. J. Clin. Pharmacol. vol. 34:29S-35S (1992). (60) Provisional application No. 60/973.229, filed on Sep. Shiraki et al., “The hypotensive mechanisms of the new anti-anginal 18, 2007. drug, N-(2-Hydroxyethyl) Nicotinamide Nitrate (SG-75) in beagle dogs.” Japan. J. Pharmacol. vol. 31:921-929 (1981). (51) Int. Cl. CFIndustries, “Material Safety Data Sheet for Urea Ammonium A6 IK3I/205 (2006.01) Nitrate Solution (UAN).” available at www.cfindustries.com/pdf UANMSDS.pdf Oct. 25, 2006. (52) U.S. Cl. Slart et al., “Nitrate Administration Increases Blood Flow in Dys USPC ...... 514/556 functional but Viable Myocardium, Leading to Improved Assessment (58) Field of Classification Search of Myocardial Viability: A PET Study,” J. Nucl. Med... vol. 47: 1307 USPC ...... 514/556 1311 (2006). See application file for complete search history. Fayers et al., “Nitrate tolerance and the links with endothelial dys function and oxidative stress.” Blackwell Publishing Ltd Br. J. Clin. (56) References Cited Pharmacol. vol. 56:620-628 (2003). Harm J. Knot. “Nitrate Tolerance in Hypertension New Insight Into a U.S. PATENT DOCUMENTS Century-Old Problem.” Circulation Research vol. 93:799-801 (2003). 3,886,040 A 5, 1975 Chihata et al. Schulz et al., “Functional and Biochemical Analysis of Endothelial 3,997,659 A 12/1976 Knohl et al. (Dys)function and NO?cGMP Signaling in Human Blood Vessels 4,146,611 A 3, 1979 Ondetti et al. With and Without Nitroglycerin Pretreatment.” Circulation Research 4,379,177 A 4/1983 McCoy et al. vol. 105: 1170-1175 (2002). 4,743,614 A 5, 1988 Terano et al. 5,500,436 A 3/1996 Schonafinger et al. (Continued) 5,679,704 A 10/1997 Schonafinger et al. 7,235,237 B2 6/2007 Loscalzo et al. 8,034,836 B2 10/2011 Kramer et al. Primary Examiner — Rei-tsang Shiao 8,048,921 B2 * 1 1/2011 Kramer et al...... 514,556 (74) Attorney, Agent, or Firm — Booth Udall Fuller, PLC 2005/0287210 A1 12, 2005 Ron 2005/0288372 A1 12, 2005 Ron (57) ABSTRACT 2005/0288373 A1 12, 2005 Ron 2006, OO29668 A1 2/2006 Ron A method for increasing the vasodilative characteristics of 2006, O1828.15 A1 8, 2006 Gladwin et al. amino acids in a human or animal is disclosed. The method 2007/O154569 A1 7/2007 Gladwin et al. includes administering to the human or animal a pharmaceu tically effective amount of an amino acid compound consist FOREIGN PATENT DOCUMENTS ing essentially of a nitrate or nitrite of an amino acid selected from the group consisting of Aspartic Acid, Cysteine, Gly CN 1631539 6, 2005 cine, Lysine, Methionine, Proline, Tyrosine, Phenylalanine, EP 13366O2 8, 2003 GB 2354441 3, 2001 Carnitine, Taurine, and Betaine. WO WO2006124161 4/2005 1 Claim, No Drawings US 8,569,369 B2 Page 2

(56) References Cited B. Sridhar, etal, “Bis(beta-alanine) HydrogenNitrate'. Acta Crystal lographica Section, 2001, pp. 1004-1006, vol. 57. OTHER PUBLICATIONS S. Narasinga Rao, et al., “Structure and Conformational Aspects of Hatanaka et al., “Stereoselective Pharmacokinetics and the Nitrates of Amino Acids and Peptides. I. Crystal Structure of Pharmacodynamics of Organic Nitrates in Rats,” J Pharmacol Exp Glycylglycine Nitrate”. Acta Crystallographica Section, 1973, pp. Ther. vol. 298(1):346-53 (2001). 2379-2388, vol. 29. Chabot et al., “Characterization of the vasodilator properties of peroxynitrite on rat pulmonary artery: role of poly (adenosine Bauer JA, et al., “Photochemical Generation of Nitric Oxide from 5'-diphosphoribose) synthase.” British Journal of Pharmacology vol. Nitro-containing Compounds: Possible Relation to Vascular 121:485-490 (1997). Photorelaxation Phenomena', Life Science, 1994, 54, 1, PL 1-4. Bauer et al., “Vascular and Hemodynamic Differences between Mostad et al., 1986, CAS: 104-197543. Organic Nitrates and Nitrites.” The Journal of Pharmacology and Pradhan et al. publication, Journal of Chemical and Engineering Experimental Therapeutics JPET vol. 280:326-331 (1997). Data, 2000, 45(1): 140-143. Niu et al., Eur J. Pharmacol 580: 169-174 (2008). Ramaswamy et al., J. Raman Spectrosc. 34:50-56 (2003). Tan et al., Vasc Pharmacol 46:338345 (2007). Rajkumart and Ramakrishnan, J. Raman Spectrosc. 31:1107-1112 Ahtee et al., J. Nutr 116:2555-2556 (1986). (2000). Bloomer et al., J Int Soc Sports Nutr 4(22): 1-6 (2007). Petrosyan et at, J. Molecular Structure 794:160-167 (2006). B. Sridhar, et al. “L-Aspartic Acid Nitrate-L-Aspartic Acid'. Acta Crystallographica Section, Dec. 2002, pp. 1372-1374, vol. 58. * cited by examiner

US 8,569,369 B2 3 4 dietary Supplement industry to increase muscle-mass gains, 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 H2N-1- forms in which Creatine may be effectively used. The R group for the Amino Acid Glutamine is: Hoc1NH, HN-C-CH-CH 10 Ornithine is a non-essential Amino Acid. That is, Ornithine is O 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 Ornithine decarboxylase. Orni in the human body and is found circulating in the blood, as 15 thine is presently used in the dietary Supplement industry to well as stored in the skeletal muscles. Glutamine plays a 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. 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. ability and limits the forms in which Glutamine may be effec 25 The R group for the Amino Acid Histidine is: tively used. Additionally, Glutamine inhibits Nitric Acid (NO) production through downregulation of eNOS synthase. The R group for the Amino Acid Leucine is:

30 H3C (r CH-CH HC Histidine is a naturally-occurring Amino Acid and is coded 35 for in DNA. Relatively small shifts in cellular pH will change Leucine is an essential Amino Acid, meaning that Leucine is the electrical charge of Histidine. For this reason, Histidine not synthesized in Vivo in animals. Accordingly, Leucine finds its way into considerable use as a coordinating ligand in must be ingested, usually as a component of proteins con metalloproteins, and also as a catalytic site in certain Sumed directly through dietary intake. Leucine plays a sig enzymes. Histidine is currently used in the dietary Supple nificant role in muscle protein synthesis. Leucine can also 40 ment industry to support carnosine production. Histidine, by inhibit protein degradation in skeletal muscle, as well as in the itself, has no vasodilating properties. Additionally, Histidine liver. Leucine is presently used in the dietary Supplement is very poorly water soluble, a fact that limits its bioavailabil industry to Supplement dietary Leucine sources. Leucine is ity and utility. Histidine is presently used in the dietary also presently used in the dietary Supplement industry to Supplement industry in the forms of single administration promote anabolism and stimulate muscle protein synthesis. 45 Histidine and Histidine HC1. Leucine, by itself, has no vasodilating properties. Leucine is The R group for the Amino Acid Beta Alanine is: also water insoluble, which reduces its bioavailability and limits the forms in which Leucine may be effectively used. The R group for the Amino Acid Norvaline is: 50 N-1S

55 Beta Alanine is the only naturally-occurring Beta Amino Norvaline is a nonessential Amino Acid. Specifically, Norva Acid. A Beta Amino Acid is one in which the Amino group is line can be independently manufactured by the human body, located at the beta position (i.e. two atoms away) from the and does not need to be obtained directly through dietary Carboxyl group. Beta Alanine is formed in vivo through the intake. Norvaline is presently used in the dietary Supplement degradation of dihydrouracil and carnosine. Beta Alanine is industry to supplement Norvaline production in the body. 60 Norvaline is also presently used in the dietary supplement the rate-limiting precursor of carnosine. Therefore, carnosine industry to inhibit the enzyme arginase and thus reduce the levels are limited by the amount of available Beta Alanine. conversion of Arginine to urea. Norvaline, by itself, has no Beta Alanine, by itself, has no vasodilating properties. Addi vasodilating properties, although it enhances the vasodilating tionally, Beat Alanine is poorly water soluble, which limits its properties of Arginine. Norvaline is also water insoluble, 65 bioavailability and utility. Beta Alanine is presently used in which reduces its bioavailability and limits the forms in the dietary Supplement industry to support carnosine produc which Leucine may be effectively used. tion. US 8,569,369 B2 5 6 The chemical structure of Agmatine is: ity might be lowered with respect to pH. Carnitine is presently used in the dietary Supplement industry to Supplement Car nitine production in the body. Carnitine is also presently used 1N1\-N NH2 in the dietary Supplement industry to improve athletic perfor HN s mance, enhance mood, and boost immune response. Various NH2 Supplemental Carnitine forms are available in the consumer marketplace. As another example, Taurine is a derivative of the sulfur Agmatine is the decarboxylation product of the Amino Acid containing amino acid Cysteine. Taurine by itself has no Arginine and is an intermediate in polyamine biosynthesis. 10 Agmatine is synthesized in the brain and stored in synaptic vasodilating properties. Taurine is presently used in the vesicles in regionally selective neurons. Agmatine is released dietary Supplement industry to Supplement Taurine produc by depolarization and is inactivated by agnatinase. Agmatine tion in the body. Taurine is also presently used in the dietary binds to alpha2-adrenoceptors and imidazoline binding sites. Supplement industry to improve athletic performance and Agmatine likewise blocks N-methyl-D-aspartic acid 15 resist muscle cramps. Various Supplemental Taurine forms (NMDA) receptor channels and other ligand-gated cationic are available in the consumer marketplace, including many channels. Additionally, agnatine inhibits nitric oxide Syn sports Supplements and energy drinks. thase, and induces the release of Some peptide hormones. As still another example, Betaine (also known as Trimethyl Agmatine modulates nitric oxide through various mecha Glycine, 2-trimethylammonioacetate, glycine betaine, nisms. Agmatine stimulates some types of nitric oxide Syn betaine anhydrous, and N.N.N-trimethylglycine) is a deriva thase (NOS) while inhibiting others. Agmatine inhibits Nitric tive of Glycine. Betaine is an N-trimethylated amino acid. Oxide production by inhibiting NOS. Agmatine is presently This quaternary ammonium exists as the Zwitterion at neutral used in the dietary Supplement industry in the forms of single pH. Betaine can be easily produced by mixing Glycine with administration Agmatine and Agmatine Sulfate. methyl iodide. The structure of Betaine is: In addition, many Amino Acid derivatives and products of 25 Amino Acid biosynthesis themselves may have biological and physiological effects. For example, Carnitine is a quaternary ammonium com pound biosynthesized from the amino acids lysine and methionine. Acetyl-L-Carnitine is an alternative form of car 30 nitine with an acetyl group coupled with the hydroxyl group of the third carbon molecule. Propionyl-L-carnitine is another Nitrates are a class of compounds that are salts of Nitric alternative form of carnitine that contains a propionyl group Acid (HNO) and at least comprise one Nitrogen atoms and coupled with the third carbon molecule. The chemical struc three Oxygenatoms (NO). Nitrites are a class of compounds tures of Carnitine, Acetyl-L-Carnitine, and Propionyl-L-car 35 that are salts of Nitrous Acid (HNO) and at least comprise nitine are as follows: one Nitrogen atom and two Oxygen atoms (NO). Nitrates and Nitrites are commercially available in various preparations and are used in various commercial applications. CH3 O In the case of ingestion by humans, Nitrate (NO) is typically H, H, I 40 reduced to Nitrite (NO) in the epithelial cells of blood ves ite--- - CH-C - C-O sels. In vivo, Nitrite (NO) reacts with a thiol donor, princi CH OH pally glutathione, to yield Nitric Oxide (NO). L-Carnitine Terminology and Definitions: CH O In describing implementations of an Amino Acid Com H, H, I 45 pound, the following terminology will be used in accordance with the definitions and explanations set out below. Notwith ite-- ––c -C-O standing, other terminology, definitions, and explanations CH3 may be found throughout this document, as well. As used herein, “Amino Acid' is a term used in its broadest 1-0 50 sense and may refer to an Amino Acid in its many different CH chemical forms including a single administration Amino Acetyl-L-Carnitine Acid, its physiologically active salts or esters, its combina CH O tions with its various salts, its tautomeric, polymeric and/or | H, H, I isomeric forms, its analog forms, its derivative forms, and/or 55 its decarboxylation products. Amino Acids comprise, by way ite--- ––c -C-O of non-limiting example: Agmatine, Beta Alanine, Arginine, CH3 Asparagine, Aspartic Acid, Cysteine, Glutamine, Glutamic =o Acid, Glycine. Histidine, Isoleucine, Leucine, Lysine, CH Methionine, PhenylBeta Alanine, Proline, Serine, Threonine, 60 Tryptophan, Tyrosine, and Valine. CH3 As used herein, “Compound is a term used in its broadest Propionyl-L-Carnitine sense and may refer to an Amino Acid in combination with one of a Nitrate and a Nitrite. As used herein, "Nitrate' is a term used in its broadest Significantly, neither carnitine nor its alternative forms 65 sense and may refer to an Nitrate in its many different chemi possess vasodilating properties. In addition, since carnitine cal forms including a salt of Nitric Acid, a single administra and its alternative forms are bipolar molecules, their solubil tion Nitrate, its physiologically active salts or esters, its com US 8,569,369 B2 7 8 binations with its various salts, its tautomeric, polymeric tical composition such as edibility, toxicity, pharmacological and/or isomeric forms, its analog forms, and/or its derivative effect, or any other aspect of a chemical, composition, or forms. Nitrate comprises, by way of non-limiting example, preparation used in implementations of a pharmaceutical many different chemical forms including dinitrate and trini composition. trate. Nitrates may be salts, or mixed salts, of Nitric Acid and Compounds/Components comprise one Nitrogenatom and three Oxygenatoms. For the A first implementation is an Arginine compound of the exemplary purposes of this disclosure, Nitrate may comprise formula: salts of Nitrate Such as Sodium nitrate, potassium nitrate, barium nitrate, calcium nitrate, and the like. For the exem plary purposes of this disclosure, Nitrate may include mixed 10 salts of Nitrate such as nitrate orotate, and the like. Addition ally, for the exemplary purposes of this disclosure, Nitrate may comprise nitrate esters such as nitroglycerine, and the like. wherein; As used herein, "Nitrite' is a term used in its broadest sense 15 and may refer to an Nitrite in its many different chemical R is the Arginine group identified and defined above: forms including a salt of Nitrous Acid, a single administration X is the Amino Acid base identified and defined above; and Nitrite, its physiologically active salts or esters, its combina Y is selected from the group consisting of a Nitrate and a tions with its various salts, its tautomeric, polymeric and/or Nitrite. isomeric forms, its analog forms, and its derivative forms. Applicants have cost-effectively synthesized Arginine Nitrite comprises, by way of non-limiting example, many Nitrate by combining nitric acid and Arginine, mixing with different chemical forms including dinitrite and trinitrite. water, and leaving to crystallize. Further nitratization can take Nitrites may be salts, or mixed salts, of Nitrous Acid and place, yielding Arginine Dinitrate or Arginine Trinitrate. An comprise one Nitrogen atom and two Oxygen atoms. For the alternative implementation may comprise using Nitrous Acid exemplary purposes of this disclosure, Nitrite may comprise 25 (HNO) instead of Nitric Acid (HNO), thus yielding Argin ine Nitrite. Arginine Nitrite has the same effects as Arginine salts of Nitrite such as sodium nitrite, potassium nitrite, Nitrate, the only difference being that it requires one less step barium nitrite, calcium nitrite, and the like. For the exemplary to yield Nitric Oxide (NO-). Mixed salts may also be used, purposes of this disclosure, Nitrite may comprise mixed salts Such as in the non-limiting example of Arginine Nitrate of Nitrite such as nitrite orotate, and the like. Additionally, for Orotate. the exemplary purposes of this disclosure, Nitrite may com 30 prise nitrite esters such as amyl nitrite, and the like. A second implementation is a Citrulline compound of the As used herein, "pharmaceutically acceptable additive' or formula: “additive' are terms used in their broadest sense. Particular implementations of the compositions described in this docu ment may also comprise an additive (e.g. one of a solubilizer, 35 an enzyme inhibiting agent, an anticoagulant, an antifoaming agent, an antioxidant, a coloring agent, a coolant, a cryopro tectant, a hydrogen bonding agent, a flavoring agent, a plas ticizer, a preservative, a Sweetener, a thickener, and combina wherein; tions thereof) and/or a carrier (e.g. one of an excipient, a 40 R is the Citruline group identified and defined above: lubricant, a binder, a disintegrator, a diluent, an extender, a X is the Amino Acid base identified and defined above; and Solvent, a suspending agent, a dissolution aid, an isotoniza Y is selected from the group consisting of a Nitrate and a tion agent, a buffering agent, a Soothing agent, an amphip Nitrite. athic lipid delivery system, and combinations thereof). These Applicants have cost-effectively synthesized Citrulline additives may be solids or liquids, and the type of additive 45 Nitrate by combining nitric acid and Citruline, mixing with may be generally chosen based on the type of administration water, and leaving to crystallize. Further nitratization can take being used. Those of ordinary skill in the art will be able to place, yielding Citrulline Dinitrate or Citrulline Trinitrate. An readily select suitable pharmaceutically effective additives alternative implementation may comprise using Nitrous Acid from the disclosure in this document. In particular implemen (HNO) instead of Nitric Acid (HNO), thus yielding Citrul tations, pharmaceutically acceptable additives may include, 50 line Nitrite. Citrulline Nitrite has the same effects as Citrul by non-limiting example, calcium phosphate, cellulose, line Nitrate, the only difference being that it requires one less Stearic acid, croScarmelose cellulose, magnesium Stearate, step to yield Nitric Oxide (NO-). Mixed salts may also be and silicon dioxide. used. Such as in the non-limiting example of Citrulline As used in this document, “pharmaceutically effective' is a Nitrate-Orotate. phrase used in its broadest sense, including, by non-limiting 55 A third implementation is a Creatine compound of the example, effective in a clinical trial, for a specific patient, or formula: only placebo-effective. As used in this document, “Pharmaceutically acceptable' is a phrase used in its broadest sense and may describe ingre dients of a pharmaceutical composition that meet Food and 60 Drug Administration (FDA) standards, United States Phar macopeial Standards (USP), US Department of Agriculture (USDA) standards for food-grade materials, commonly wherein; accepted Standards of the nutritional Supplement industry, R is the Creatine group identified and defined above: industry standards, botanical standards, or standards estab 65 X is the Amino Acid base identified and defined above; and lished by any individual. These standards may delineate Y is selected from the group consisting of a Nitrate and a acceptable ranges of aspects of ingredients of a pharmaceu Nitrite. US 8,569,369 B2 10 Applicants have cost-effectively synthesized Creatine Nitrate by combining nitric acid and Creatine, mixing with R water, and leaving to crystallize. Further nitratization can take | | . Y place, yielding Creatine Dinitrate or Creatine Trinitrate. An X alternative implementation may comprise using Nitrous Acid (HNO) instead of Nitric Acid (HNO), thus yielding Creat wherein; ine Nitrite. Creatine Nitrite has the same effects as Creatine R is the Norvaline group identified and defined above; Nitrate, the only difference being that it requires one less step X is the Amino Acid base identified and defined above; and to yield Nitric Oxide (NO ). Mixed salts may also be used, Y is selected from the group consisting of a Nitrate and a such as in the non-limiting example of Creatine Nitrate-Oro 10 Nitrite. tate. Applicants have cost-effectively synthesized Norvaline A fourth implementation is a Glutamine compound of the Nitrate by combining nitric acid and Norvaline, mixing with formula: water, and leaving to crystallize. Further nitratization can take 15 place, yielding Norvaline Dinitrate or Norvaline Trinitrate. An alternative implementation comprises Substituting Nitrous Acid (HNO) for Nitric Acid (HNO), thus yielding Norvaline Nitrite. Norvaline Nitrite has the same effects as Norvaline 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-limiting example of Norvaline wherein; Nitrate-Orotate. R is the Glutamine group identified and defined above: A seventh implementation is an Ornithine compound of the X is the Amino Acid base identified and defined above; and formula: Y is selected from the group consisting of a Nitrate and a 25 Nitrite. Applicants have cost-effectively synthesized Glutamine Nitrate by combining nitric acid and Glutamine, mixing with water, and leaving to crystallize. Further nitratization can take 30 place, yielding Glutamine Dinitrate or Glutamine Trinitrate. wherein; An alternative implementation comprises using Nitrous Acid R is the Ornithine group identified and defined above: (HNO) instead of Nitric Acid (HNO), thus yielding X is the Amino Acid base identified and defined above; and Glutamine Nitrite. Glutamine Nitrite has the same effects as Y is selected from the group consisting of a Nitrate and a Glutamine Nitrate, the only difference being that it requires 35 Nitrite. one less step to yield Nitric Oxide (NO ). Mixed salts may Applicants have cost-effectively synthesized Ornithine also be used, such as in the non-limiting example of Nitrate by combining nitric acid and Ornithine, mixing with Glutamine Nitrate-Orotate. water, and leaving to crystallize. Further nitratization can take A fifth implementation is a Leucine compound of the for place, yielding Ornithine Dinitrate or Ornithine Trinitrate. An mula: 40 alternative implementation comprises using Nitrous Acid (HNO) instead of Nitric Acid (HNO), thus yielding Orni thine Nitrite. Ornithine Nitrite has the same effects as Orni thine Nitrate, the only difference being that it requires one less step to yield Nitric Oxide (NO-). Mixed salts may also be 45 used. Such as in the non-limiting example of Ornithine Nitrate-Orotate. An eighth implementation is a Histidine compound of the wherein; formula: R is the Leucine group identified and defined above: X is the Amino Acid base identified and defined above; and 50 Y is selected from the group consisting of a Nitrate and a Nitrite. Applicants have cost-effectively synthesized Leucine Nitrate by combining nitric acid and Leucine, mixing with 55 wherein; water, and leaving to crystallize. Further nitratization can take R is the Histidine group identified and defined above: place, yielding Leucine Dinitrate or Leucine Trinitrate. An X is the Amino Acid base identified and defined above; and alternative implementation comprises Substituting the Amino Y is selected from the group consisting of a Nitrate and a Acids Valine or Isoleucine for Leucine. Another alternative Nitrite. implementation comprises substituting Nitrous Acid (HNO) 60 Applicants have cost-effectively synthesized Histidine for Nitric Acid (HNO), thus yielding Leucine Nitrite. Leu Nitrate by combining nitric acid and Histidine, mixing with cine Nitrite has the same effects as Leucine Nitrate, the only water, and leaving to crystallize. Further nitratization can take difference being that it requires one less step to yield Nitric place, yielding Histidine Dinitrate or Histidine Trinitrate. An Oxide (NO ). Mixed salts may also be used, such as in the alternative implementation comprises using Nitrous Acid non-limiting example of Leucine Nitrate-Orotate. 65 (HNO) instead of Nitric Acid (HNO), thus yielding Histi A sixth implementation is a Norvaline compound of the dine Nitrite. Histidine Nitrite has the same effects as Histidine formula: Nitrate, the only difference being that it requires one less step US 8,569,369 B2 11 12 to yield Nitric Oxide (NO ). Mixed salts may also be used, alternative implementation may comprise using Nitrous Acid such as in the non-limiting example of Histidine Nitrate (HNO) instead of Nitric Acid (HNO), thus yielding Car Orotate. nitine Nitrite. Carnitine Nitrite has the same effects as Car A ninth implementation is a Beta Alanine compound of the nitine Nitrate, the only difference being that it requires one formula: 5 less step to yield Nitric Oxide (NO ). Mixed salts may also be used, such as in the non-limiting example of Carnitine Nitrate-Orotate. In addition, it will be understood that alter native implementations comprising Acetyl-L-Carnitine and/ or Propionyl-L-carnitine in combination with one of a Nitrate 10 and a Nitrite are likewise possible in accordance with these disclosures. wherein; Another implementation is a Taurine compound of the R is the Beta Alanine group identified and defined above: formula: X is the Amino Acid base identified and defined above; and Y is selected from the group consisting of a Nitrate and a 15 Nitrite. O Applicants have cost-effectively synthesized Beta Alanine \-N-NHe Y Nitrate by combining nitric acid and Beta Alanine, mixing HO 1. \, with water, and leaving to crystallize. Further nitratization can take place, yielding Beta Alanine Dinitrate or Beta Ala nine Trinitrate. An alternative implementation comprises wherein; using Nitrous Acid (HNO) instead of Nitric Acid (HNO), Y is selected from the group consisting of a Nitrate and a thus yielding Beta Alanine Nitrite. Beta Alanine Nitrite has Nitrite. the same effects as Beta Alanine Nitrate, the only difference 25 Applicants have cost-effectively synthesized Taurine being that it requires one less step to yield Nitric Oxide Nitrate by combining nitric acid and Taurine, mixing with (NO—). Mixed salts may also be used, such as in the non water, and leaving to crystallize. Further nitratization can take limiting example of Beta Alanine Nitrate-Orotate. place, yielding Taurine Dinitrate or Taurine Trinitrate. An A tenth implementation is an Agmatine compound of the alternative implementation may comprise using Nitrous Acid formula: 30 (HNO) instead of Nitric Acid (HNO), thus yielding Taurine Nitrite. Taurine Nitrite has the same effects as Taurine 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-limiting example of Taurine Nitrate-Orotate. 35 Still another implementation is a Betaine compound of the formula: wherein; Y is selected from the group consisting of a Nitrate and a CH, Nitrite. 40 N Y Applicants have cost-effectively synthesized Agmatine M O Nitrate by combining nitric acid and Agmatine, mixing with water, and leaving to crystallize. Further nitratization can take place, yielding Agmatine Dinitrate or Agmatine Trinitrate. An alternative implementation comprises using Nitrous Acid wherein; (HNO) instead of Nitric Acid (HNO), thus yielding Agma 45 Y is selected from the group consisting of a Nitrate and a tine Nitrite. Agmatine Nitrite has the same effects as Agma Nitrite. tine Nitrate, the only difference being that it requires one less Applicants have cost-effectively synthesized Betaine step to yield Nitric Oxide (NO-). Mixed salts may also be Nitrate by combining nitric acid and Betaine, mixing with used. Such as in the non-limiting example of Agmatine water, and leaving to crystallize. Further nitratization can take Nitrate-Orotate. 50 place, yielding Betaine Dinitrate or Betaine Trinitrate. An A first implementation is a Carnitine compound of the alternative implementation comprises using Nitrous Acid formula: (HNO) instead of Nitric Acid (HNO), thus yielding Betaine Nitrite. Betaine Nitrite has the same effects as Betaine Nitrate, the only difference being that it requires one less step CH O 55 to yield Nitric Oxide (NO-). Mixed salts may also be used, | H, H, Il such as in the non-limiting example of Betaine Nitrate-Oro HC-N'-C-CH-C-C-O Y tate. Compositions and/or formulations may be administered in CH OH any form, including one of a capsule, a cachet, a pill, a tablet, 60 a powder, a granule, a pellet, a bead, a particle, a troche, a wherein; lozenge, a pastille, a solution, an elixir, a syrup, a tincture, a Y is selected from the group consisting of a Nitrate and a Suspension, an emulsion, a mouthwash, a spray, a drop, an Nitrite. ointment, a cream, a gel, a paste, a transdermal patch, a Applicants have cost-effectively synthesized Carnitine Suppository, a pessary, cream, a gel, a paste, a foam, and Nitrate by combining nitric acid and Carnitine, mixing with 65 combinations thereof for example. Compositions and/or for water, and leaving to crystallize. Further nitratization can take mulations may also include a acceptable additive (e.g. one of place, yielding Carnitine Dinitrate or Carnitine Trinitrate. An a solubilizer, an enzyme inhibiting agent, an anticoagulant, an US 8,569,369 B2 13 14 antifoaming agent, an antioxidant, a coloring agent, a coolant, Amino Acid, Nitric or Nitrous Acid and water, and pharma a cryoprotectant, a hydrogen bonding agent, a flavoring ceutically acceptable ingredient. agent, a plasticizer, a preservative, a Sweetener, a thickener, It should be appreciated that any of the components of and combinations thereof) and/or a acceptable carrier (e.g. particular implementations of an Amino Acid Compound one of an excipient, a lubricant, a binder, a disintegrator, a may be used as Supplied commercially, or may be prepro diluent, an extender, a solvent, a Suspending agent, a disso cessed by, by non-limiting example, any of the methods and lution aid, an isotonization agent, a buffering agent, a Sooth techniques of agglomeration, air Suspension chilling, air Sus ing agent, an amphipathic lipid delivery system, and combi pension drying, balling, coacervation, comminution, com nations thereof). pression, pelletization, cryopelletization, extrusion, granula 10 tion, homogenization, inclusion Compoundation, Implementations of Amino Acid Nitrate and/or Nitrite lyophilization, melting, mixed, molding, pan coating, Solvent Compounds may also be synthesized or created in a wide dehydration, Sonication, spheronization, spray chilling, spray variety of manners, and may be made from a wide variety of congealing, spray drying, or other processes known in the art materials. Those of ordinary skill in the art will readily be able depending in part on the dosage form desired. The various to select appropriate materials and methods to manufacture 15 components may also be pre-coated or encapsulated as and use the compounds disclosed herein. known in the art. It will also be clear to one of ordinary skill Dosage Forms in the art that appropriate additives may also be introduced to Implementations of Amino Acid Compounds may conve the composition or during the processes to facilitate the niently be presented in unit dosage form. Unit dosage formu preparation of the dosage forms, depending on the need of the lations may be those containing a daily dose or unit, a daily individual process. Sub-dose, or an appropriate fraction thereof, of the adminis Mixing the measured quantities of Amino Acid, Nitric or tered components as described herein. Nitrous Acid and water, and pharmaceutically acceptable A dosage unit may include an Amino Acid Compound. In additives or inert ingredients, may involve any number of addition, a dosage unit may include an Amino Acid Com steps and implementing components, and may be accom pound admixed with a pharmaceutically acceptable 25 plished readily from this disclosure. For the exemplary pur additive(s), and/or any combination thereof. poses of this disclosure, mixed the measured quantities of The dosage units may be in a form suitable for administra Amino Acid, Nitric or Nitrous Acid and water, and pharma tion by standard routes. In general, the dosage units may be ceutically acceptable additives or inertingredients, may com administered, by non-limiting example, by the topical (in prise combining the measured quantities of m Amino Acid, cluding buccaland Sublingual), transdermal, oral, rectal, oph 30 Nitric or Nitrous Acid and water, and pharmaceutically thalmic (including intravitreal or intracameral), nasal, vagi acceptable additives or inert ingredients, under the influence nal, and/or parenteral (including subcutaneous, of physical, ultrasonic, or electrostatic forces to create a intramuscular, intravenous, intradermal, intratracheal, and desired degree of intermingling and/or chemical reaction of epidural) routes. the Amino Acid, Nitric or Nitrous Acid and water and any For the exemplary purposes of this disclosure, oral delivery 35 pharmaceutically acceptable ingredients. The mixed may be may be a particularly advantageous delivery route for admin accomplished when the Amino Acid, Nitric or Nitrous Acid istration to humans and animals of implementations of a and water and/or any pharmaceutically acceptable ingredi pharmaceutical composition, optionally formulated with ents are in a solid, liquid, or semisolid state. appropriate pharmaceutically acceptable additives to facili Separating the Amino Acid Compound into discrete quan tate administration. 40 tities for distribution may involve any number of steps and Manufacture implementing components, and separating the Amino Acid Implementations of an Amino Acid Compound may be Compound into discrete quantities for distribution may be made using conventional or other procedures. Accordingly, accomplished readily from this disclosure. For the exemplary although there are a variety of method implementations for purposes of this disclosure, separating the Amino Acid Com producing pharmaceutical compositions, for the exemplary 45 pound into discrete quantities for distribution may involve purposes of this disclosure, a method implementation for utilizing a specific piece of equipment, for example, a con producing an Amino Acid Compound may comprise: mea ventional tablet forming apparatus to shape the formed com Suring specific quantities of Amino Acid, Nitric or Nitrous position into individual tablets, each containing a desired Acid and water mixed in a specific order the measured quan dose of Amino Acid Compound. The separating process may tities of Amino Acid, Nitric or Nitrous Acid and water, and 50 be accomplished when the Amino Acid Compound is in a any additional pharmaceutically acceptable additives or inert Solid, liquid, or semisolid state. ingredients, and then separating the pharmaceutical compo Those of ordinary skill in the art will be able to readily sition into discrete quantities for distribution and/or admin select manufacturing equipment and pharmaceutically istration. acceptable additives or inert ingredients to manufacture Measuring specific quantities of Amino Acid, Nitric or 55 implementations of an Amino Acid Compound. For the Nitrous Acid and water, and pharmaceutically acceptable exemplary purposes of this disclosure, some examples of additives or inert ingredients, may involve any number of pharmaceutically acceptable additives or inert ingredients steps and implementing components, and measuring specific and manufacturing process are included below, particularly quantities of Amino Acid, Nitric or Nitrous Acid and water, those that relate to manufacture of implementations of an and pharmaceutically acceptable additives or inert ingredi 60 Amino Acid Compound in tablet form. Notwithstanding the ents, may be accomplished readily from this disclosure. For specific examples given, it will be understood that those of the exemplary purposes of this disclosure, measuring specific ordinary skill in the art will readily appreciate how to manu quantities of Amino Acid, Nitric or Nitrous Acid and water, facture implementations of an Amino Acid Compound and pharmaceutically acceptable additives or inert ingredi according to the other methods of administration and delivery ents, may comprise using a scale, a Solid or liquid dispensing 65 disclosed in this document. apparatus, or other measurement device capable of measuring A particular implementation of an Amino Acid Compound Solid mass or liquid volume to produce a desired quantity of may include a lubricant. Lubricants are any anti-sticking

US 8,569,369 B2 17 18 Empirical studies indicate that Nitrates are useful for their vasodilation may, in turn, provide better circulation and dis vasolidating effects. Common Nitrates include nitroglycerin tribution of Arginine in the body. Absorption may be and isosorbide dinitrate. Nitrates exert their vasodilating improved since Amino Acid salts with inorganic acids are effect through their reduction to Nitrites. In vivo, Nitrates are much more water soluble than single administration Amino reduced to Nitrites and, in the blood vessels epithelial cells, Acids. Applicants have also discovered that the vasodilating Nitrite reacts with a thiol donor (mainly glutathione) to yield effect of Arginine Nitrate manifests faster than that of single Nitric Oxide. Louis J. Ignarro, “After 130 years, the Molecu administration Arginine, and as fast as any nitrate, since the lar Mechanism of Action of Nitroglycerin is Revealed’ (Jun. 11, 2002) available at http://www.pnas.org/cgi/content/full/ NO-group of the salt requires minimal conversion to yield 99/12/7816?ck inck, the contents of which are hereby incor Nitric Oxide. Additionally a much lesser dose may be porated herein by reference. 10 required for vasodilation to take place, compared to the single The Nitric Oxide inhibiting characteristics of the Amino administration of Arginine. Likewise, the development of Acid Glutamine have been well documented in a number of tolerance to the nitrate component of the molecule may be studies. In particular, a Mar. 28, 2006 report in the American prevented with the presence of Arginine. Arginine Nitrate Journal of Physiology has found that Glutamine inhibits may promote vasodilation through production of Nitric Nitric Oxide production by downregulation of eNOS syn 15 Oxide by two different pathways, the Arginine citrullization thase. Masao Kakoki, et al. “Amino acids as Modulators of pathway and the nitrate reduction pathway. Arginine Nitrate Endothelium-Derived Nitric Oxide.” available at http://ajpre may likewise be more water Soluble than single administra nal physiology.org/cgi/content/full/291/2/F297, the contents tion Arginine. of which are hereby incorporated by reference. Accordingly, Applicants have discovered that the Citrul A January 2006 Journal of Nutrition report indicates that line compound according to the second implementation, the Amino Acid Leucine promotes anabolism and stimulates when ingested, provides enhanced Nitric Oxide (NO ) pro muscle protein synthesis. Michael J. Rennie, et al. duction while providing improved vasodilation effects over “Branched-Chain Amino Acids as Fuels and Anabolic Sig single administration of Citrulline, the single administration nals in Human Muscle' available at http://jn.nutrition.org/ of Nitrates, or the single administration of Nitrites. Improved cgi/content/full/136/1/264S, the contents of which are hereby 25 vasodilation may, in turn, provide better circulation and dis incorporated by reference. tribution of Citrulline in the body. Absorption may be Empirical studies indicate that the Amino Acid Norvaline 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/ 30 vasodilation to take place, compared to the single adminis 86/3/745?ijkey=5d 134456b7443ca36c80926946 tration of Citrulline or nitrates. Citrulline Nitrate is likewise 2276e532549798&key type2=tf ipsecsha, the contents of more water soluble than single administration Citruline. which 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 35 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 nals in Human Muscle' available at http://jn.nutrition.org/ Nitrates, or the single administration of Nitrites. Improved cgi/content/full/136/1/264S, the contents of which are hereby vasodilation may, in turn, provide better circulation and dis incorporated by reference. 40 tribution of Creatine in the body. Absorption may be Empirical studies indicate that the Amino Acids Beta-Beta improved since Amino Acid salts with inorganic acids are Alanine and L-Histidine Support carnosine production. M. much more water soluble than single administration Amino Dunnett, “Influence of Oral Beta-Beta Alanine and L-Histi Acids. Additionally a much lesser dose may be required for dine Supplementation on the Carnosine Content of the Glu vasodilation to take place, compared to the single adminis teus Medius' Equine Veterinary Journal Supplement, avail 45 tration of nitrates. Creatine Nitrate is likewise more water able at http://www.ncbi.nlm.nih.gov/sites/entrez?Db= soluble than single administration Creatine. pubmed&Cmd=ShowDetailView&TermToSearch= Accordingly, Applicants have discovered that the 10659307&ordinalpos=4&itool=EntrezSystem2.PEntrez. Glutamine compound according to the fourth implementa Pubmed. Pubmed, the contents of which are hereby incorpo tion, when ingested, counters the Nitric Oxide (NO ) inhib rated by reference. 50 iting characteristics of Glutamine. Absorption of Glutamine Empirical studies further indicate that the Amino Acids may be improved since Amino Acid salts with inorganic acids Beta Alanine and L-Histidine increase muscle power, recu are much more water Soluble than single administration peration and stamina. Yoshihiro Suzuki “High Level of Skel Amino Acids. Additionally a much lesser dose may be etal Muscle Carnosine Contributes to the Latter Half of Exer required for vasodilation to take place, compared to the single cise Performance During 30-S Maximal Cycle Ergometer 55 administration of nitrates. Glutamine Nitrate may likewise be Sprinting in the Japanese Journal of Physiology, available at more water soluble than single administration Glutamine. http://www.ncbi.nlm.nih.gov/sites/entrez?Db-pubmed& Accordingly, Applicants have discovered that the Leucine Cmd=ShowDetailView&TermTOS earch=12139778& Ordi compound according to the fifth implementation, when nalpos= 4&itool=EntrezSystem2.PEntrez. Pubmed. ingested, provides enhanced Nitric Oxide (NO ) production Pubmed ResultsPanel. Pubmed RVDocSum, the contents 60 while providing improved vasodilation effects over single of which are hereby incorporated by reference. administration of Leucine, the single administration of Accordingly, Applicants have discovered that the Arginine Nitrates, or the single administration of Nitrites. Improved compound according to the first implementation, when vasodilation may, in turn, provide better circulation and dis ingested, provides enhanced Nitric Oxide (NO ) production tribution of Leucine in the body. Absorption may be improved while providing improved vasodilation effects over single 65 since Amino Acid salts with inorganic acids are much more administration of Arginine, the single administration of water Soluble than single administration Amino Acids. Addi Nitrates, or the single administration of Nitrites. Improved tionally a much lesser dose may be required for vasodilation US 8,569,369 B2 19 20 to take place, compared to the single administration of provide better circulation and distribution of Beta Alanine in nitrates. Leucine Nitrate is likewise more water soluble than the body. Applicants have likewise discovered that the Beta single administration Leucine. Alanine compound according to the tenth implementation, Accordingly, Applicants have discovered that the Norval when ingested, promotes carnosine production, thus increas ine compound according to the sixth implementation, when 5 ing muscle power, endurance and recuperation. Absorption ingested, promotes vasodilation through the inhibition of may be improved since Amino Acid salts with inorganic acids arginase, while promoting Nitric Oxide formation via the are much more water soluble than single administration nitrate mechanism. Improved vasodilation may, in turn, pro Amino Acids. Applicants have also discovered that Beta Ala vide better circulation and distribution of Norvaline in the nine Nitrate begins acting as fast as any other nitrate, since the body. Absorption may be improved since Amino Acid salts 10 NO-group of the salt requires minimal conversion to yield with inorganic acids are much more water soluble than single Nitric Oxide. Additionally, a much lesser dose may be administration Amino Acids. Additionally a much lesser dose required for vasodilation to take place, compared to the single may be required for vasodilation to take place, compared to administration of nitrates. Beta Alanine Nitrate may likewise the single administration of nitrates. Norvaline Nitrate may be more water soluble than single administration Beta Ala likewise be more water soluble than single administration 15 nine. Norvaline. Accordingly, Applicants have discovered that the Agma Accordingly, Applicants have discovered that the Orni tine compound according to the eighth implementation, when thine compound according to the seventh implementation, ingested, counteracts the Nitric Oxide inhibiting effect of when ingested, provides an additional vasodilation mecha single administration Agmatine. Absorption may be nism, reducing the amount of Ornithine needed and the improved since Amino Acid salts with inorganic acids are amount of time needed for the vasodilating properties to much more water soluble than single administration Amino manifest. Improved vasodilation may, in turn, provide better Acids. Applicants have also discovered that Agmatine Nitrate circulation and distribution of Ornithine in the body. Absorp begins acting as fast as any other nitrate, since the NO-group tion may be improved since Amino Acid salts with inorganic of the salt requires minimal conversion to yield Nitric Oxide. acids are much more water soluble than single administration 25 Agmatine Nitrate may likewise be more water soluble than Amino Acids. Applicants have also discovered that Ornithine single administration Agmatine. Nitrate begins acting as fast as any other nitrate, since the Accordingly, Applicants have discovered that the Carnitine NO-group of the salt requires minimal conversion to yield compound according to an implementation, when ingested, Nitric Oxide. Additionally, a much lesser dose may be provides enhanced Nitric Oxide (NO-) production while required for vasodilation to take place, compared to the single 30 providing improved vasodilation effects over single adminis administration of nitrates. Ornithine Nitrate may likewise be tration of Carnitine, the single administration of Nitrates, or more water soluble than single administration Ornithine. the single administration of Nitrites. Improved vasodilation Accordingly, Applicants have discovered that the Histidine may, in turn, provide better circulation and distribution of compound according to the eighth implementation, when Carnitine in the body. Absorption may be improved since ingested, provides a vasodilation mechanism. Vasodilation 35 Amino Acid derivative salts with inorganic acids may be may, in turn, provide better circulation and distribution of much more water soluble than single administration Amino Histidine in the body. Applicants have likewise discovered Acid derivatives. Applicants have also discovered that the that the Histidine compound according to the ninth imple vasodilating effect of Carnitine Nitrate and Taurine Nitrate mentation, when ingested, promotes carnosine production, manifests as fast as any nitrate, since the NO. group of the thus increasing muscle power, endurance and recuperation. 40 salt requires minimal conversion to yield Nitric Oxide. Like Absorption may be improved since Amino Acid salts with wise, the development of tolerance to the nitrate component inorganic acids are much more water soluble than single of the molecule may be prevented with the presence of Car administration Amino Acids. Applicants have also discovered nitine and/or Taurine. that Histidine Nitrate begins acting as fast as any other nitrate, The invention claimed is: since the NO-group of the salt requires minimal conver 45 1. A method for increasing the vasodilative characteristics sion to yield Nitric Oxide. Additionally, a much lesser dose of amino acids in a human or animal, the method comprising may be required for vasodilation to take place, compared to administering to the human or animal a pharmaceutically the single administration of nitrates. Histidine Nitrate may effective amount of an amino acid compound consisting likewise be more water soluble than single administration essentially of a nitrate or nitrite of an amino acid selected Histidine. 50 from the group consisting of Aspartic Acid, Cysteine, Gly Accordingly, Applicants have discovered that the Beta Ala cine, Lysine, Methionine, Proline, Tyrosine, Phenylalanine, nine compound according to the ninth implementation, when Carnitine, Taurine, and Betaine. ingested, provides vasodilation. Vasodilation may, in turn, US00856.9369C1 (12) EX PARTE REEXAMINATION CERTIFICATE (10997th) United States Patent (10) Number: US 8,569,369 C1 Kramer et al. (45) Certificate Issued: *Nov. 28, 2016

(54) AMINO ACID COMPOUNDS (51) Int. Cl. A6II 3L/205 (2006.01) (75) Inventors: Ronald Kramer, Phoenix, AZ (US); C07D 233/64 (2006.01) Alexander(GR) Nikolaidis, New Kalfikratia (52)52) U.S. Cl.C CPC ...... C07D 233/64 (2013.01) (73) Assignee: THERMOLIFE INTERNATIONAL, (58) Field of Classification Search LLC, Phoenix, AZ (US) None See application file for complete search history. Reexamination Request: No. 90/013,517, Jul. 1, 2015 (56) References Cited Reexamination Certificate for: To view the complete listing of prior art documents cited Patent No.: 8,569,369 during the proceeding for Reexamination Control Number Issued: Oct. 29, 2013 90/013,517, please refer to the USPTO's public Patent Appl. No.: 13/468,231 Application Information Retrieval (PAIR) system under the Filed: May 10, 2012 Display References tab. (*) Notice: This patent is subject to a terminal dis claimer. Primary Examiner — Gary Kunz Related U.S. Application Data (63) Continuation-in-part of application No. 12/946,153, (57) ABSTRACT filed on Nov. 15, 2010, now Pat. No. 8,178,572, A method for increasing the vasodilative characteristics of which is a continuation of application No. amino acids in a human or animal is disclosed. The method 12/336,938, filed on Dec. 17, 2008, now Pat. No. includes administering to the human or animal a pharma 8.034.836, which is a continuation of application No. ceutically effective amount of an amino acid compound 11/950,273, filed on Dec. 4, 2007, now Pat. No. consisting essentially of a nitrate or nitrite of an amino acid 7,777,074. selected from the group consisting of Aspartic Acid, Cyste (60) Provisional application No. 60/973.229, filed on Sep. ine, Glycine, Lysine, Methionine, Proline, Tyrosine, Phenyl 18, 2007. alanine, Carnitine, Taurine, and Betaine. US 8,569,369 C1 1. 2 EX PARTE Acid, Cysteine, Glycine, Lysine, Methionine, Proline, Tyro REEXAMINATION CERTIFICATE sine, Phenylalanine, Carnitine, Taurine, and Betaine. 2. The method of claim I, wherein the amino acid com pound is a nitrate of Aspartic Acid. THE PATENT IS HEREBY AMENDED AS 3. The method of claim I, wherein the amino acid com INDICATED BELOW. pound is a nitrate of Cysteine. Matter enclosed in heavy brackets appeared in the 4. The method of claim I, wherein the amino acid com patent, but has been deleted and is no longer a part of the pound is a nitrate of Glycine. patent; matter printed in italics indicates additions made 5. The method of claim I, wherein the amino acid com to the patent. 10 pound is a nitrate of Methionine. 6. The method of claim I, wherein the amino acid com AS A RESULT OF REEXAMINATION, IT HAS BEEN pound is a nitrate of Proline. DETERMINED THAT: 7. The method of claim I, wherein the amino acid com pound is a nitrate of Tvrosine. Claim 1 is determined to be patentable as amended. 15 8. The method of claim I, wherein the amino acid com New claims 2-11 are added and determined to be pound is a nitrate of Phenylalanine. patentable. 9. The method of claim I, wherein the amino acid com 1. A method for increasing the vasodilative characteristics pound is a nitrate of Carnitine. of amino acids in a human or animal, the method com 10. The method of claim I, wherein the amino acid prising orally administering to the human or animal a 20 compound is a nitrate of Taurine. pharmaceutically effective amount of an amino acid com II. The method of claim I, wherein the amino acid pound consisting essentially of a nitrate or nitrite of an compound is a nitrate of Betaine. amino acid selected from the group consisting of Aspartic k k k k k