USOO8048921B2

(12) United States Patent (10) Patent No.: US 8,048,921 B2 Kramer et al. (45) Date of Patent: Nov. 1, 2011

(54) AMINO ACID COMPOUNDS Fetih et al., "Nitric oxide donors can enhance the intestinal transport and absorption of insulin and Asu 1.7-eel calcitonin in rats.” Journal of Controlled Release vol. 106:287-297 (2005). (76) Inventors: Ronald Kramer, Phoenix, AZ (US); Fetih et al., “Excellent Absorption Enhancing Characteristics of NO Alexander Nikolaidis, New Kallikratia Donors for Improving the Intestinal Absorption of Poorly Absorbable (GR) Compound Compared with Conventional Absorption Enhancers.” Drug Metab. Pharmacokinet, vol. 21(3):222-229 (2006). (*) Notice: Subject to any disclaimer, the term of this Aniya et al., “Evaluation of Nitric Oxide Formation from Nitrates in Pig Coronary Arteries,” Jpn. J. Pharmacal. vol. 71: 101-107 (1996). patent is extended or adjusted under 35 T.F. Luscher, "Endogenous and exogenous nitrates and their role in U.S.C. 154(b) by 400 days. myocardial ischaemia.” Br. J. Clin. Pharmacol. vol. 34:29S-35S (1992). (21) Appl. No.: 12/337,012 Shiraki et al., “The hypotensive mechanisms of the new anti-anginal drug, N-(2-Hydroxyethyl) Nicotinamide Nitrate (Sg-75) in beagle (22) Filed: Dec. 17, 2008 dogs.” Japan. J. Pharmacol. vol. 31:921-929 (1981). CFIndustries, “Material Safety Data Sheet for Urea Ammonium Nitrate Solution (UAN).” available at www.cfindustries.com/pdf (65) Prior Publication Data UANMSDS.pdf Oct. 25, 2006. US 2009/O13767OA1 May 28, 2009 Slart et al., “Nitrate Administration Increases Blood Flow in Dys functional but Viable Myocardium, Leading to Improved Assessment of Myocardial Viability: A Pet Study.” J. Nucl. Med... vol. 47: 1307 Related U.S. Application Data 1311 (2006). (63) Continuation-in-part of application No. 1 1/950,273, Fayers et al., “Nitrate tolerance and the links with endothelial dys filed on Dec. 4, 2007, now Pat. No. 7,777,074. function and oxidative stress.” Blackwell Publishing Ltd Br. J. Clin. Pharmacol. vol. 56:620-628 (2003). (60) Provisional application No. 60/973.229, filed on Sep. Harm J. Knot. “Nitrate Tolerance in Hypertension New Insight Into a 18, 2007. Century-Old Problem.” Circulation Research vol. 93:799-801 (2003). Schulz et al., “Functional and Biochemical Analysis of Endothelial (51) Int. Cl. (Dys)function and NO?cGMP Signaling in Human Blood Vessels A6 IK3I/205 (2006.01) With and Without Nitroglycerin Pretreatment.” Circulation Research C07C 229/00 (2006.01) vol. 105: 1170-1175 (2002). (52) U.S. Cl...... 514/556; 562/567 Hatanaka et al., “Stereoselective Pharmacokinetics and (58) Field of Classification Search ...... 514/556; Pharmacodynamics of Organic Nitrates in Rats,” J Pharmacol Exp 562/567 Ther. vol. 298(1):346-53 (2001). “Glyceryl trinitrate-leaflet print—Patient UK.’ available at http:// See application file for complete search history. www.patient.co.uk/printer.asp?doc=30003883. Chabot et al., “Characterization of the vasodilator properties of (56) References Cited peroxynitrite on rat pulmonary artery: role of poly (adenosine 5'-diphosphoribose) synthase.” British Journal of Pharmacology vol. U.S. PATENT DOCUMENTS 121:485-490 (1997). 4,379,177 A 4/1983 McCoy et al. Bauer et al., “Vascular and Hemodynamic Differences between 4,743,614 A 5, 1988 Terano et al. Organic Nitrates and Nitrites.” The Journal of Pharmacology and OTHER PUBLICATIONS Experimental Therapeutics JPET vol. 280:326-331 (1997). Niu et al., Eur J. Pharmacol 580: 169-174 (2008). Xu et al., 2005, CAS: 143: 103285.* Tan et al., Vasc Pharmacol 46:338-345 (2007). Jablecka et al., MedSci Monit 10(1):CR29-32 (2004). Ahtee et al., J. Nutr 116:2555-2556 (1986). Maynard et al., J. Nutr. 131:287-290 (2001). Bloomer et al., J Int Soc Sports Nutr 4(22): 1-6 (2007). Rytlewski et al., European Journal of Obstetrics & Gynecology and Ramaswamy et al., J. Raman Spectrosc. 34:50-56 (2003). Reproductive Biology 138:23-28 (2008). Rajkumar and Ramakrishnan, J. Raman Spectrosc. 31:1107-1112 Schwedheim et al., Br J Clin Pharmacol 65(1):51-59 (2007). (2000). Smith et al., J. Thorac Cardiovasc. Surg 132:58-65 (2006). Petrosyan et at, J. Molecular Structure 794:160-167 (2006). Rytlewski et al., Eur J. Clin Invest 35 (1):32-37 (2005). Ming et al., Circulation 110:3708-3714 (2004). * cited by examiner Romero et al., Cardiovascular Drug Reviews 24(3-4):275-290 (2006). Primary Examiner — Rei-tsang Shiao Oka et al., Vasc Med 10:265-274 (2005). (74) Attorney, Agent, or Firm — Booth Udall, PLC Hayashi et al., PNAS 102(38): 13681-13686 (2005). Grasemann et al., Eur Respir J 25:62-68 (2005). (57) ABSTRACT Boger, J. Nutr 137:1650S-1655S (2007). Beghetti et al., J. Thorac Cardiovasc. Surg 132(6): 1501-1502 (2006). Carnitine and Taurine Compounds are described. The Car Larsen et al., B. Acta Physiol 191(1):59-66 (2007). nitine Compound comprises Carnitine and one of a Nitrate Berge, Journal of Pharmaceutical Sciences, Jan. 1977, vol. 66, No. 1. and a Nitrite. The Taurine Compound comprises Taurine and Takahashi et al., “Characterization of the influence of nitric oxide one of a Nitrate and a Nitrite. donors on intestinal absorption of macromolecules.” International Journal of Pharmaceutics vol. 286:89-97 (2004). 6 Claims, No Drawings US 8,048,921 B2 1. 2 AMINO ACID COMPOUNDS Taurine Compound comprising Taurine and one of a Nitrate and a Nitrite to the human or animal. CROSS REFERENCE TO RELATED The foregoing and other aspects, features, and advantages APPLICATIONS will be apparent to those of ordinary skill in the art from the DESCRIPTION and from the CLAIMS. This application is a continuation-in-part application of the earlier U.S. Utility patent application to Ronald Kramer, et. DESCRIPTION al. entitled “Amino Acid Compounds, application Ser. No. 11/950,273, filed Dec. 4, 2007, now pending, which applica Overview tion claims the benefit of the filing date of U.S. Provisional 10 Compounds containing both a carboxyl group and an Patent Application 60/973.229 entitled “Amino Acid Com amino group are typically known as Amino Acids. Amino pounds to Alexander Nikolaidis and Ronald Kramer which Acids typically have the basic formula X-R, wherein X is: was filed on Sep. 18, 2007, the disclosures of which is hereby incorporated entirely herein by reference. 15 CH-COOH BACKGROUND

1. Technical Field Aspects of this document relate generally to Taurine and Amino Acids typically differ from one another with respect Carnitine Compounds. to the structure of the R group. It is the structure of the R group 2. Background that typically determines the individuality and character of It is desirable to design new Taurine and Carnitine com each Amino Acid. pounds that have properties lacking in conventional Taurine In addition, many Amino Acid derivatives and products of and Carnitine compounds, conventional Nitrate compounds, Amino Acid biosynthesis themselves may have biological conventional Nitrite compounds, and in single-administra 25 and physiological effects. tion Taurine and Carnitine products. For example, Carnitine is a quaternary ammonium com pound biosynthesized from the amino acids lysine and SUMMARY methionine. Acetyl-L-Carnitine is an alternative form of car nitine with an acetyl group coupled with the hydroxyl group In one aspect, this document features a carnitine compound 30 of the third carbon molecule. Propionyl-L-carnitine is another comprising Carnitine and one of a Nitrate and a Nitrite. alternative form of carnitine that contains a propionyl group Particular embodiments may include one or more of the coupled with the third carbon molecule. The chemical struc following. The Carnitine compound may further comprise a tures of Carnitine, Acetyl-L-Carnitine, and Propionyl-L-car pharmaceutically acceptable additive, wherein the additive is nitine are as follows: one of a carrier, excipient, binder, colorant, flavoring agent, 35 preservative, buffer, dilutant, and combinations thereof. The Carnitine compound may be in the form of a capsule, tablet, CH O pill, liquid, liquid Suspension, vapor, gas, powder, granulate | H, H, I or pulverulence. ic--- -CH-C-C-O In another aspect, this document features a carnitine com 40 pound comprising Taurine and one of a Nitrate and a Nitrite. CH3 OH Particular embodiments may include one or more of the L-Camitine following. The Taurine compound may further comprise a CH3 O pharmaceutically acceptable additive, wherein the additive is H, H, I one of a carrier, excipient, binder, colorant, flavoring agent, 45 ic--c ––c -C-O preservative, buffer, dilutant, and combinations thereof. The CH3 Taurine compound may be in the form of a capsule, tablet, pill, liquid, liquid Suspension, vapor, gas, powder, granulate =o or pulverulence. CH3 In yet another aspect, this document features a method for 50 Acetyl-L-Carmitine increasing water solubility of one of Carnitine and Taurine in CH3 O a human or animal, which comprises administering a phar H, H, I maceutically effective amount of one of a Carnitine Com ic--c ––c -C-Ot pound comprising Carnitine and one of a Nitrate and a Nitrite CH and a Taurine Compound comprising Taurine and one of a 55 Nitrate and a Nitrite to the human or animal. Particular embodiments may include one or more of the =o following. Increasing water solubility may further comprise CH2 increasing the bioabsorption of one of Carnitine and Taurine CH in a human or animal. Increasing water Solubility may further 60 comprise increasing the vasodilative characteristics of one of Propionyl-L-Camitine Carnitine and Taurine in a human or animal. In still another aspect, this document features a method for Significantly, neither carnitine nor its alternative forms preventing the development of nitrate tolerances in a human possess vasodilating properties. In addition, since carnitine or animal, which comprises administering a pharmaceuti 65 and its alternative forms are bipolar molecules, their solubil cally effective amount of one of a Carnitine Compound com ity might be lowered with respect to pH. Carnitine is presently prising Carnitine and one of a Nitrate and a Nitrite and a used in the dietary Supplement industry to Supplement Car US 8,048,921 B2 3 4 nitine production in the body. Carnitine is also presently used barium nitrate, calcium nitrate, and the like. For the exem in the dietary Supplement industry to improve athletic perfor plary purposes of this disclosure, Nitrate may include mixed mance, enhance mood, and boost immune response. Various salts of Nitrate such as nitrate orotate, and the like. Addition Supplemental Carnitine forms are available in the consumer ally, for the exemplary purposes of this disclosure, Nitrate marketplace. may comprise nitrate esters such as nitroglycerine, and the In addition to the foregoing example, Taurine is a derivative like. of the Sulfur-containing amino acid Cysteine. Taurine by As used herein, "Nitrite' is a term used in its broadest sense itselfhas no vasodilating properties. Taurine is presently used and may refer to an Nitrite in its many different chemical forms including a salt of Nitrous Acid, a single administration in the dietary Supplement industry to Supplement Taurine 10 production in the body. Taurine is also presently used in the Nitrite, its physiologically active salts or esters, its combina dietary Supplement industry to improve athletic performance tions with its various salts, its tautomeric, polymeric and/or isomeric forms, its analog forms, and its derivative forms. and resist muscle cramps. Various Supplemental Taurine Nitrite comprises, by way of non-limiting example, many forms are available in the consumer marketplace, including 15 different chemical forms including dinitrite and trinitrite. many sports Supplements and energy drinks. Nitrites may be salts, or mixed salts, of Nitrous Acid and Nitrates are a class of compounds that are salts of Nitric comprise one Nitrogen atom and two Oxygen atoms. For the Acid (HNO) and at least comprise one Nitrogen atoms and exemplary purposes of this disclosure, Nitrite may comprise three Oxygenatoms (NO). In addition, Nitrites are a class of salts of Nitrite such as Sodium nitrite, potassium nitrite, compounds that are salts of Nitrous Acid (HNO) and at least barium nitrite, calcium nitrite, and the like. For the exemplary comprise one Nitrogen atom and two Oxygen atoms (NO). purposes of this disclosure, Nitrite may comprise mixed salts Nitrates and Nitrites are commercially available in various of Nitrite such as nitrite orotate, and the like. Additionally, for preparations and are used in various commercial applications. the exemplary purposes of this disclosure, Nitrite may com In the case of ingestion by humans, Nitrate (NO) is typically prise nitrite esters such as amyl nitrite, and the like. 25 As used herein, “pharmaceutically acceptable additive' or reduced to Nitrite (NO) in the epithelial cells of blood ves “additive' are terms used in their broadest sense. Particular sels. In vivo, Nitrite (NO) reacts with a thiol donor, princi implementations of the compositions described in this docu pally glutathione, to yield Nitric Oxide (NO). ment may also comprise an additive (e.g. one of a solubilizer, an enzyme inhibiting agent, an anticoagulant, an antifoaming TERMINOLOGY AND DEFINITIONS 30 agent, an antioxidant, a coloring agent, a coolant, a cryopro In describing implementations of an Amino Acid Com tectant, a hydrogen bonding agent, a flavoring agent, a plas pound, the following terminology will be used in accordance ticizer, a preservative, a Sweetener, a thickener, and combina tions thereof) and/or a carrier (e.g. one of an excipient, a with the definitions and explanations set out below. Notwith lubricant, a binder, a disintegrator, a diluent, an extender, a standing, other terminology, definitions, and explanations 35 Solvent, a suspending agent, a dissolution aid, an isotoniza may be found throughout this document, as well. tion agent, a buffering agent, a Soothing agent, an amphip As used herein, “Amino Acid' is a term used in its broadest athic lipid delivery system, and combinations thereof). These sense and may refer to an Amino Acid in its many different additives may be solids or liquids, and the type of additive chemical forms including a single administration Amino 40 may be generally chosen based on the type of administration Acid, its physiologically active salts or esters, its combina being used. Those of ordinary skill in the art will be able to tions with its various salts, its tautomeric, polymeric and/or readily select suitable pharmaceutically effective additives isomeric forms, its analog forms, its derivative forms, its from the disclosure in this document. In particular implemen biosynthesis products and/or its decarboxylation products. tations, pharmaceutically acceptable additives may include, Amino Acids comprise, by way of non-limiting example: 45 by non-limiting example, calcium phosphate, cellulose, Agmatine, Beta Alanine, Arginine, Asparagine, Aspartic Stearic acid, croScarmelose cellulose, magnesium Stearate, Acid, Cysteine, Glutamine, Glutamic Acid, Glycine. Histi and silicon dioxide. dine, Isoleucine, Leucine, Lysine, Methionine, PhenylBeta As used in this document, “pharmaceutically effective' is a Alanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, phrase used in its broadest sense, including, by non-limiting and Valine. 50 example, effective in a clinical trial, for a specific patient, or As used herein, “Compound is a term used in its broadest only placebo-effective. sense and may refer to an Amino Acid in combination with As used in this document, “Pharmaceutically acceptable' one of a Nitrate and a Nitrite. is a phrase used in its broadest sense and may describe ingre As used herein, "Nitrate' is a term used in its broadest 55 dients of a pharmaceutical composition that meet Food and sense and may refer to an Nitrate in its many different chemi Drug Administration (FDA) standards, United States Phar cal forms including a salt of Nitric Acid, a single administra macopeial Standards (USP), US Department of Agriculture tion Nitrate, its physiologically active salts or esters, its com (USDA) standards for food-grade materials, commonly binations with its various salts, its tautomeric, polymeric accepted Standards of the nutritional Supplement industry, and/or isomeric forms, its analog forms, and/or its derivative 60 industry standards, botanical standards, or standards estab forms. Nitrate comprises, by way of non-limiting example, lished by any individual. These standards may delineate many different chemical forms including dinitrate and trini acceptable ranges of aspects of ingredients of a pharmaceu trate. Nitrates may be salts, or mixed salts, of Nitric Acid and tical composition such as edibility, toxicity, pharmacological comprise one Nitrogenatom and three Oxygenatoms. For the 65 effect, or any other aspect of a chemical, composition, or exemplary purposes of this disclosure, Nitrate may comprise preparation used in implementations of a pharmaceutical salts of Nitrate Such as Sodium nitrate, potassium nitrate, composition. US 8,048,921 B2 5 6 Compounds/Components Solvent, a suspending agent, a dissolution aid, an isotoniza A first implementation is a Carnitine compound of the tion agent, a buffering agent, a Soothing agent, an amphip formula: athic lipid delivery system, and combinations thereof). Implementations of Carnitine and Taurine Nitrate and/or Nitrite Compounds may also be synthesized or created in a CH3 O wide variety of manners, and may be made from a wide variety of materials. Those of ordinary skill in the art will Y readily be able to select appropriate materials and methods to manufacture and use the compounds disclosed herein. CH3 OH Dosage Forms 10 Implementations of Carnitine and Taurine Compounds may conveniently be presented in unit dosage form. Unit wherein; dosage formulations may be those containing a daily dose or Y is selected from the group consisting of a Nitrate and a unit, a daily Sub-dose, or an appropriate fraction thereof, of Nitrite. the administered components as described herein. Applicants have cost-effectively synthesized Carnitine 15 A dosage unit may include a Carnitine and/or a Taurine Nitrate by combining nitric acid and Carnitine, mixing with Compound. In addition, a dosage unit may include a Car water, and leaving to crystallize. Further nitratization can take nitine and Taurine Compound admixed with a pharmaceuti place, yielding Carnitine Dinitrate or Carnitine Trinitrate. An cally acceptable additive(s), and/or any combination thereof. alternative implementation may comprise using Nitrous Acid The dosage units may be in a form Suitable for administra (HNO) instead of Nitric Acid (HNO), thus yielding Car tion by standard routes. In general, the dosage units may be nitine Nitrite. Carnitine Nitrite has the same effects as Car administered, by non-limiting example, by the topical (in nitine Nitrate, the only difference being that it requires one cluding buccaland Sublingual), transdermal, oral, rectal, oph less step to yield Nitric Oxide (NO ). Mixed salts may also thalmic (including intravitreal or intracameral), nasal, vagi be used, such as in the non-limiting example of Carnitine nal, and/or parenteral (including Subcutaneous, Nitrate-Orotate. In addition, it will be understood that alter 25 intramuscular, intravenous, intradermal, intratracheal, and native implementations comprising Acetyl-L-Carnitine and/ epidural) routes. or Propionyl-L-carnitine in combination with one of a Nitrate For the exemplary purposes of this disclosure, oral delivery may be a particularly advantageous delivery route for admin and a Nitrite are likewise possible in accordance with these istration to humans and animals of implementations of a disclosures. pharmaceutical composition, optionally formulated with Another implementation is a Taurine compound of the 30 formula: appropriate pharmaceutically acceptable additives to facili tate administration. Manufacture Implementations of Carnitine and Taurine Compounds may be made using conventional or other procedures. 35 Accordingly, although there are a variety of method imple HO 1. \, mentations for producing pharmaceutical compositions, for the exemplary purposes of this disclosure, a method imple mentation for producing a Carnitine and Taurine Compounds wherein; may comprise: measuring specific quantities of Carnitine Y is selected from the group consisting of a Nitrate and a 40 and/or Taurine, Nitric or Nitrous Acid and water mixed in a Nitrite. specific order the measured quantities of Carnitine and/or Applicants have cost-effectively synthesized Taurine Taurine, Nitric or Nitrous Acid and water, and any additional Nitrate by combining nitric acid and Taurine, mixing with pharmaceutically acceptable additives or inert ingredients, water, and leaving to crystallize. Further nitratization can take and then separating the pharmaceutical composition into dis place, yielding Taurine Dinitrate or Taurine Trinitrate. An 45 crete quantities for distribution and/or administration. alternative implementation may comprise using Nitrous Acid Measuring specific quantities of Carnitine and/or Taurine, Nitric or Nitrous Acid and water, and pharmaceutically (HNO) instead of Nitric Acid (HNO), thus yielding Taurine acceptable additives or inert ingredients, may involve any Nitrite. Taurine Nitrite has the same effects as Taurine Nitrate, number of steps and implementing components, and measur the only difference being that it requires one less step to yield ing specific quantities of Carnitine and/or Taurine, Nitric or Nitric Oxide (NO ). Mixed salts may also be used, such as 50 Nitrous Acid and water, and pharmaceutically acceptable in the non-limiting example of Taurine Nitrate-Orotate. additives or inert ingredients, may be accomplished readily Compositions and/or formulations of the present invention from this disclosure. For the exemplary purposes of this dis may be administered in any form, including one of a capsule, closure, measuring specific quantities of Carnitine and/or a cachet, a pill, a tablet, a powder, a granule, a pellet, a bead, Taurine, Nitric or Nitrous Acid and water, and pharmaceuti a particle, a troche, a lozenge, a pastille, a solution, an elixir, 55 cally acceptable additives or inert ingredients, may comprise a syrup, a tincture, a Suspension, an emulsion, a mouthwash, using a scale, a solid or liquid dispensing apparatus, or other a spray, a drop, an ointment, a cream, a gel, a paste, a trans measurement device capable of measuring Solid mass or liq dermal patch, a Suppository, a pessary, cream, a gel, a paste, a uid volume to produce a desired quantity of Carnitine and/or foam, and combinations thereof for example. Compositions Taurine, Nitric or Nitrous Acid and water, and pharmaceuti and/or formulations of the present invention may also include 60 cally acceptable ingredient. a acceptable additive (e.g. one of a solubilizer, an enzyme It should be appreciated that any of the components of inhibiting agent, an anticoagulant, an antifoaming agent, an particular implementations of Carnitine and Taurine Com antioxidant, a coloring agent, a coolant, a cryoprotectant, a pounds may be used as Supplied commercially, or may be hydrogen bonding agent, a flavoring agent, a plasticizer, a preprocessed by, by non-limiting example, any of the meth preservative, a Sweetener, a thickener, and combinations 65 ods and techniques of agglomeration, air suspension chilling, thereof) and/or a acceptable carrier (e.g. one of an excipient, air Suspension drying, balling, coacervation, comminution, a lubricant, a binder, a disintegrator, a diluent, an extender, a compression, pelletization, cryopelletization, extrusion, US 8,048,921 B2 7 8 granulation, homogenization, inclusion Compoundation, Particular implementations of Carnitine and Taurine Com lyophilization, melting, mixed, molding, pan coating, Solvent pounds may also include a binder. Binders are any agents dehydration, Sonication, spheronization, spray chilling, spray used to impart cohesive qualities to powdered material congealing, spray drying, or other processes known in the art through particle-particle bonding. Binders may include, for depending in part on the dosage form desired. The various 5 example, matrix binders (e.g. dry starch, dry Sugars), film components may also be pre-coated or encapsulated as binders (e.g. celluloses, bentonite. Sucrose), and chemical known in the art. It will also be clear to one of ordinary skill binders (e.g. polymeric cellulose derivatives, such as methyl in the art that appropriate additives may also be introduced to cellulose, carboxy methyl cellulose, and hydroxy propyl cel the composition or during the processes to facilitate the lulose); and other Sugar, gelatin, non-cellulosic binders and preparation of the dosage forms, depending on the need of the 10 individual process. the like. Mixing the measured quantities of Carnitine and/or Tau Disintegrators may be used in particular implementations rine, Nitric or Nitrous Acid and water, and pharmaceutically of Carnitine and Taurine Compounds to facilitate the breakup acceptable additives or inert ingredients, may involve any or disintegration of tablets after administration. Disintegra number of steps and implementing components, and may be 15 tors may include, for example, starch, starch derivatives, accomplished readily from this disclosure. For the exemplary clays (e.g. bentonite), algins, gums (e.g. guar gum), cellulose, purposes of this disclosure, mixed the measured quantities of cellulose derivatives (e.g. methyl cellulose, carboxymethyl Carnitine and/or Taurine, Nitric or Nitrous Acid and water, cellulose), croScarmellose Sodium, croscarmellose cellulose, and pharmaceutically acceptable additives or inert ingredi and other organic and inorganic materials. ents, may comprise combining the measured quantities of Implementations of Carnitine and Taurine Compounds Carnitine and/or Taurine, Nitric or Nitrous Acid and water, may include diluents, or any inert Substances added to and pharmaceutically acceptable additives or inert ingredi increase the bulk of the Carnitine and Taurine Compounds to ents, under the influence of physical, ultrasonic, or electro make a tablet a practical size for compression. Diluents may static forces to create a desired degree of intermingling and/or include, for example, calcium phosphate, calcium sulfate, chemical reaction of the Carnitine and/or Taurine, Nitric or 25 lactose, mannitol, magnesium Stearate, potassium chloride, Nitrous Acid and water and any pharmaceutically acceptable and citric acid, among other organic and inorganic materials. ingredients. The mixed may be accomplished when the Car Buffering agents may be included in Carnitine and Taurine nitine and/or Taurine, Nitric or Nitrous Acid and water and/or Compounds and may be any one of an acid and a base, where any pharmaceutically acceptable ingredients are in a solid, the acid is, for example, propionic acid, p-toluenesulfonic liquid, or semisolid state. 30 acid, Salicylic acid, Stearic acid, Succinic acid, tannic acid, Separating Carnitine and Taurine Compounds into discrete tartaric acid, thioglycolic acid, or toluenesulfonic acid, and quantities for distribution may involve any number of steps the base is, for example, ammonium hydroxide, potassium and implementing components, and separating t Carnitine hydroxide, Sodium hydroxide, Sodium hydrogen carbonate, and Taurine Compounds into discrete quantities for distribu aluminum hydroxide, calcium carbonate, and other organic tion may be accomplished readily from this disclosure. For 35 and inorganic chemicals. the exemplary purposes of this disclosure, separating the Implementations of Carnitine and Taurine Compounds Amino Acid Compound into discrete quantities for distribu may also be administered through use of amphipathic lipid tion may involve utilizing a specific piece of equipment, for delivery systems (such as liposomes and unilamellar example, a conventional tablet forming apparatus to shape the vesicles), caplet systems, oral liquid systems, parenteral and/ formed composition into individual tablets, each containing a 40 or intravenous systems, topical systems (creams, gels, trans desired dose of Carnitine and Taurine Compounds. The sepa dermal patches, etc.), intranasal systems, rectal or vaginal rating process may be accomplished when the Carnitine and systems, and many other delivery methods and/or systems Taurine Compounds are in a Solid, liquid, or semisolid state. known to those of ordinary skill in the art. Those of ordinary Those of ordinary skill in the art will be able to readily skill in the art will readily be able to select additional phar select manufacturing equipment and pharmaceutically 45 maceutically acceptable additives to enable delivery of acceptable additives or inert ingredients to manufacture implementations of a pharmaceutical composition from the implementations of Carnitine and Taurine Compounds. For disclosure in this document. the exemplary purposes of this disclosure, some examples of With respect to delivery of particular implementations of pharmaceutically acceptable additives or inert ingredients Carnitine and Taurine Compounds, for the exemplary pur and manufacturing process are included below, particularly 50 poses of this disclosure, tablets may be utilized. Tablets are those that relate to manufacture of implementations of Car any solid pharmaceutical dosage form containing a pharma nitine and Taurine Compounds in tablet form. Notwithstand ceutically acceptable active agent or agents to be adminis ing the specific examples given, it will be understood that tered with or without suitable pharmaceutically acceptable those of ordinary skill in the art will readily appreciate how to additives and prepared either by compression or molding manufacture implementations of Carnitine and Taurine Com 55 methods well known in the art. Tablets have been in wide pounds according to the other methods of administration and spread use and remain popular as a dosage form because of delivery disclosed in this document. the advantages afforded both to the manufacturer (e.g., sim A particular implementation of Carnitine and Taurine plicity and economy of preparation, stability, and conve Compounds may include a lubricant. Lubricants are any anti nience in packaging, shipping, and dispensing) and the Sticking agents, glidants, flow promoters, and the like mate 60 patient (e.g., accuracy of dosage, compactness, portability, rials that perform a number of functions in tablet manufac blandness of taste, and ease of administration). Although ture, for example, Such as improving the rate of flow of the tablets are most frequently discoid in shape, they may also be tablet granulation, preventing adhesion of the tablet material round, oval, oblong, cylindrical, rectangular or triangular, for to the Surface of the dies and punches, reducing interparticle example. The tablets may be optionally scored so that they friction, and facilitating the ejection of the tablets from the die 65 may be separated into different dosages. They may differ cavity. Lubricants may comprise, for example, magnesium greatly in size and weight depending on the amount of the Stearate, calcium Stearate, talc, and colloidal silica. pharmaceutically acceptable active agent or agents present US 8,048,921 B2 10 and the intended route of administration. They are divided Nitrite reacts with a thiol donor (mainly glutathione) to yield into two general classes, (1) compressed tablets, and (2) Nitric Oxide. Louis J. Ignarro, “After 130 years, the Molecu molded tablets. lar Mechanism of Action of Nitroglycerin is Revealed’ (Jun. Tablets and other orally discrete dosage forms, such as 11, 2002) available at http://www.pnas.org/cgi/content/full/ capsules, cachets, pills, granules, pellets, beads, and particles, 99/12/7816?ck inck, the contents of which are hereby incor for example, may optionally be coated with one or more porated herein by reference. enteric coatings, seal coatings, film coatings, barrier coatings, The Nitric Oxide inhibiting characteristics of the Amino compress coatings, fast disintegrating coatings, or enzyme Acid Glutamine have been well documented in a number of degradable coatings for example. Multiple coatings may be studies. In particular, a Mar. 28, 2006 report in the American applied for desired performance. Further, dosage forms may 10 Journal of Physiology has found that Glutamine inhibits be designed for, by non-limiting example, immediate release, Nitric Oxide production by downregulation of eNOS syn pulsatile release, controlled release, extended release, thase. Masao Kakoki, et al. “Amino acids as Modulators of delayed release, targeted release, synchronized release, or Endothelium-Derived Nitric Oxide.” available at http://ajpre targeted delayed release. For release/absorption control, car nal physiology.org/cgi/content/full/291/2/F297, the contents riers may be made of various component types and levels or 15 of which are hereby incorporated by reference. thicknesses of coats. Such diverse carriers may be blended in A January 2006 Journal of Nutrition report indicates that a dosage form to achieve a desired performance. In addition, the Amino Acid Leucine promotes anabolism and stimulates the dosage form release profile may be effected by a poly muscle protein synthesis. Michael J. Rennie, et al. meric matrix composition, a coated matrix composition, a “Branched-Chain Amino Acids as Fuels and Anabolic Sig multi-particulate composition, a coated multiparticulate nals in Human Muscle' available at http://jn.nutrition.org/ composition, an ion-exchange resin-based composition, an cgi/content/full/136/1/264S, the contents of which are hereby osmosis-based composition, or a biodegradable polymeric incorporated by reference. composition. Empirical studies indicate that the Amino Acid Norvaline While manufacture of implementations of Carnitine and inhibits the enzyme arginase and thus decreases the rate of Taurine Compounds have been described in particular 25 conversion of the Amino Acid Arginine to urea. Takeyori sequences of steps and/or in particular forms, it will be under Saheki, et al. “Regulation of Urea Synthesis in Rat Liver stood that such manufacture is not limited to the specific order available at http://b.oxfordjournals.org/cgi/content/abstract/ of steps or forms as disclosed. Any steps or sequences of steps 86/3/745?ijkey=5d 134456b7443ca36c809269462276e5325 of manufacture of implementations of Carnitine and Taurine 49798& key type2=tf ipsecsha, the contents of which are Compounds in any form are given as examples of possible 30 hereby incorporated by reference. steps or sequences of steps or potential forms and not as An October 2004 Journal of Nutrition report indicates that limitations, since many possible manufacturing processes the Amino Acid Ornithine promotes anabolism and stimu and sequences of steps may be used to manufacture Carnitine lates muscle protein synthesis. Michael J. Rennie, et al. and Taurine Compound implementations in a wide variety of “Branched-Chain Amino Acids as Fuels and Anabolic Sig forms. 35 nals in Human Muscle' available at http://jn.nutrition.org/ Use cgi/content/full/136/1/264S, the contents of which are hereby Implementations of Carnitine and Taurine Compounds are incorporated by reference. particularly useful in increasing vasodilation and blood flow Empirical studies indicate that the Amino Acids Beta-Beta in humans and animals. However, implementations are not Alanine and L-Histidine Support carnosine production. M. limited to uses relating to vasodilation modification, and the 40 Dunnett, “Influence of Oral Beta-Beta Alanine and L-Histi like. Rather, any description relating to the foregoing is for the dine Supplementation on the Carnosine Content of the Glu exemplary purposes of this disclosure. It will be understood teus Medius' Equine Veterinary Journal Supplement, avail that implementations of Carnitine and Taurine Compounds ableathttp://www.ncbi.nlm.nih.gov/sites/entrez?Db= may encompass a variety of uses and are not limited in their pubmed&Cmd=ShowDetailView&Term ToSearch= uses. For example, possible uses may be, by non-limiting 45 10659307&ordinalpos=4&itool-EntrezSystem2.PEntrez. example, improved athletic performance, increased distribu Pubmed. Pubmed, the contents of which are hereby incorpo tion to muscles, faster action than single-administration Car rated by reference. nitine and/or Taurine, enhanced water Solubility, prevention Empirical studies further indicate that the Amino Acids of Nitrate tolerance, and/or countering Nitric Oxide inhibit Beta Alanine and L-Histidine increase muscle power, recu ing effects of certain Amino Acids. 50 peration and stamina.ii Yoshihiro Suzuki “High Level of In conventional preparations of Nitrate compounds, “tol Skeletal Muscle Carnosine Contributes to the Latter Half of erance a particular side effect, has been observed in many Exercise Performance During 30-S Maximal Cycle Ergom patients. This is unfortunate because the effectiveness of eter Sprinting in the Japanese Journal of Physiology, avail Nitrate on vasodilation is well documented. “Tolerance' able at http://www.ncbi.nlm.nih.gov/sites/entrez? occurs when a Subjects reaction to Nitrate decreases so that 55 Db pubmed&Cmd=ShowDetailView&TermToSearch= larger doses are required to achieve the same effect. A Mar. 3, 12139778&ordinalpos=4&itool-EntrezSystem2.PEntrez. 2000 report in the British Journal of Pharmacology indicates Pubmed. Pubmed ResultsPanel. Pubmed RVDocSum, the that “tolerance to the dilator effects of nitrates remains a contents of which are hereby incorporated by reference. persisting therapeutic problem.” Raymond J. MacAllister Accordingly, Applicants have discovered that the Carnitine Arginine and Nitrate Tolerance' available at http://www.na 60 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 Carnitine, the single administration of vasolidating effects. Common Nitrates include nitroglycerin Nitrates, or the single administration of Nitrites. Improved and isosorbide dinitrate. Nitrates exert their vasodilating 65 vasodilation may, in turn, provide better circulation and dis effect through their reduction to Nitrites. In vivo, Nitrates are tribution of Carnitine in the body. Absorption may be reduced to Nitrites and, in the blood vessels epithelial cells, improved since Amino Acid derivative salts with inorganic US 8,048,921 B2 11 12 acids may be much more water Soluble than single adminis nitrite of Carnitine and a Taurine Compound consisting tration Amino Acid derivatives. Applicants have also discov essentially of a nitrate or nitrite of Taurine to the human or ered that the vasodilating effect of Carnitine Nitrate and Tau animal. rine Nitrate manifests as fast as any nitrate, since the NO 4. The method of claim 3, wherein increasing water solu group of the salt requires minimal conversion to yield Nitric bility further comprises increasing the bioabsorption of one Oxide. Likewise, the development of tolerance to the nitrate of Carnitine and Taurine in a human or animal. component of the molecule may be prevented with the pres 5. The method of claim 3, wherein increasing water solu ence of Carnitine and/or Taurine. bility further comprises increasing the vasodilative character What is claimed is: istics of one of Carnitine and Taurine in a human or animal. 1. A Carnitine Compound consisting essentially of a nitrate 10 6. A method for treating the development of nitrate toler or nitrite of Carnitine. ances in a human or animal, which comprises administering a 2. A Taurine Compound consisting essentially of a nitrate pharmaceutically effective amount of one of a Carnitine or nitrite of Taurine. Compound consisting essentially of a nitrate or nitrite of 3. A method for increasing water solubility of one of Car Carnitine and a Taurine Compound consisting essentially of a nitine and Taurine in a human or animal, which comprises 15 nitrate or nitrite of Taurine to the human or animal. administering a pharmaceutically effective amount of one of a Carnitine Compound consisting essentially of a nitrate or