US007608641B2
`
`(12) Ulllted States Patent
`Miller et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 7,608,641 B2
`*Oct. 27, 2009
`
`(54) CREATINE ORAL SUPPLEMENTATION
`USING CREATINE HYDROCHLORIDE SALT
`
`(75) Inventors: Donald W. Miller, Winnipeg (CA);
`Jonathan L. Vennerstrom, Omaha, NE
`
`(52) US. Cl. .................................................... .. 514/565
`(58) Field of Classi?cation Search ................ .. 514/565
`See application ?le for complete search history.
`_
`References Clted
`
`(56)
`
`Mark C- Faulkner, Madlson,
`
`5,817,329 A 10/1998 Gardiner
`
`(73) Assignee: Board of Regents of the University of
`Nebraska’ Lincoln’ NE (Us)
`
`( >x< ) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 888 days.
`
`This patent is subject to a terminal dis-
`Claimem
`
`_
`(21) Appl' NO" 10/846’782
`
`(22) F1led:
`
`May 14, 2004
`
`6,136,339 A 10/2000 Gardiner
`6,620,425 B1
`9/2003 Gardiner
`6,784,209 B1
`8/2004 Gardiner et a1.
`6,897,334 B2 *
`5/2005 Vennerstrom ............. .. 560/169
`FOREIGN PATENT DOCUMENTS
`
`0222135
`WO
`_
`_
`* cited by examlner
`
`3/2002
`
`Primary ExamineriKevin Weddington
`(74) Attorney, Agent, or FirmiHanify & King, RC.
`
`(57)
`
`ABSTRACT
`
`(65)
`
`Pnor Pubhcatlon Data
`US 2004/0242691 A1
`Dec. 2, 2004
`
`Related U-s- Application Data
`(60) Provisional application No. 60/470,356, ?led on May
`15 2003'
`’
`(51) Int. Cl.
`A61K 31/195
`
`(2006.01)
`
`Creatine oral supplementation using creatine hydrochloride
`salt, that may be added to a liquid or other beverage, or may
`be also used as an additive to solid oral dosages, or as a
`supplement, and Which may be consumed by the athlete, or
`other party lookmg for lmmedlate supplememanon of
`strength, and may be added as a supplement Within feed to
`livestock, in the veterinary area.
`
`7 Claims, N0 Drawings
`
`Vireo Systems, Inc. Ex. 2009 - 001
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`

`
`US 7,608,641 B2
`
`1
`CREATINE ORAL SUPPLEMENTATION
`USING CREATINE HYDROCHLORIDE SALT
`
`CROSS REFERENCE TO RELATED
`APPLICATION
`
`This non-provisional patent application claims priority to
`the provisional application for patent having Ser. No. 60/470,
`356, Which Was ?led on May 15, 2003.
`
`BACKGROUND OF THE INVENTION
`
`Dietary supplementation With creatine is an approved and
`accepted means for increasing muscle performance, and
`increasing muscle mass. Most current commercial applica
`tions involving creatine supplementation use the creatine
`monohydrate form as the primary embodiment. A limitation
`of creatine supplements using the creatine monohydrate form
`is that the products have loW aqueous solubility and require
`relatively large doses of creatine be consumed With large
`amounts of ?uid. The physiochemical properties of creatine
`monohydrate are such that oral absorption is limited. There
`are other salt forms including creatine citrate (creatine effer
`vescent) and creatine pyruvate that have been patented and
`marketed as improvements over creatine monohydrate.
`Despite the various salt forms currently marketed, there is an
`unmet need for an improved form of creatine that could be
`taken in a more convenient dosage form and have better oral
`absorption characteristics.
`
`SUMMARY OF THE INVENTION
`
`This invention relates principally to the use of creatine
`hydrochloride salt for application to aqueous solutions foruse
`as a beverage in the sports environment, liquid meal replace
`ment, nutritional energy bars, and other forti?ed foods.
`In essence, this invention relates to the usage of a granular
`precipitate consisting of creatine hydrochloride salt in a high
`purity and yield. More speci?cally, the creatine hydrochlo
`ride salt, When added to a solution, and used as a beverage or
`other form of drink, functions as a nutritional supplement for
`enhancing muscle performance and developing muscle mass
`in both humans and livestock.
`It is, therefore, the principle object of this invention to
`utiliZe creatine hydrochloride salt, apart from other forms of
`creatine, but in this instance, having high aqueous solubility
`so as to readily mix With any liquid, or beverage, and having
`application in the ?eld of athletics to enhance developed and
`generated strength.
`Another object of this invention is the application of hydro
`chloride salts, of creatine form, that may be added as a feed
`additive When fed to livestock, or other animals.
`These and other objects may become more apparent to
`those skilled in the art upon revieW of the summary of the
`invention as provided herein and upon undertaking a study of
`the description of its preferred embodiment.
`
`DESCRIPTION OF THE PREFERRED
`EMBODIMENT
`
`The present invention involves a process for the production
`of the hydrochloride salt form of creatine. The process uses
`creatine monohydrate and acetyl chloride as the reactants
`and, ethanol as the preferred solvent. The product of this
`reaction is a granular precipitate consisting of the creatine
`hydrochloride salt in high purity and yield.
`
`20
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`25
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`30
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`35
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`45
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`50
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`55
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`60
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`65
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`2
`The invention also involves an application or use of the
`creatine hydrochloride salt as a nutritional supplement for
`enhancing muscle performance and muscle mass in both
`humans and livestock. What sets this creatine hydrochloride
`salt apart from the other forms of creatine is its high aqueous
`solubility. Studies in the inventors’ laboratory indicate that
`the aqueous solubility of the creatine hydrochloride is 150
`mg/ml or greater, While that of creatine monohydrate and
`creatine citrate salt is at least an order of magnitude loWer
`(approximately 10-15 mg/ml). As the loW oral absorption of
`creatine supplements are believed to be attributable in part to
`reduced solubility, the creatine hydrochloride Would be
`expected to have better oral absorption properties. An alter
`nate embodiment of the process uses anhydrous creatine. An
`alternate embodiment of the process uses other short chain
`alcohols selected from methanol, propanol, butanol, isopro
`panol, among others to replace the ethanol solvent.
`Various other applications for use With this type of a salt,
`other than in the sports beverage area, may include its appli
`cation as a feed additive in livestock. Certainly, based upon
`What is noW knoWn about the product, it Would have imme
`diate applications in the solid oral dosage supplementation
`area, as an additive or a feed supplement in livestock feed. Or,
`it may be added into a liquid, or any Water, that is fed to the
`livestock, during there consumption of liquids and solids.
`This is contemplated Within the essence of this invention
`that the formulation for the oral supplementation of this
`invention could be provided in a solid oral dosage form, such
`as in a capsule form, or tablets, for treatment requirements
`When taken by the human, animal, and the like. This is knoWn
`in the art. The formulation for the creatine oral supplementa
`tion, using the Creatine Hydrochloride Salt, is CrHCl. The
`formulation could be added into a beverage in addition the
`CrHCl may be provided as an ingredient to a sports drink,
`liquid meal replacement, or the like, and as can be under
`stood. Furthermore, the concept of this invention for use of
`this formulation Within a supplementation can be used and
`applied for nutritional and energy purposes. Furthermore, the
`composition could be added as a forti?cation to other foods.
`Finally, it is likely that this composition could be added as a
`feed supplement, to further enhance the energy requirements
`of the horses, and other animals, as may be desired and
`required.
`The product of this reaction of creatine monohydrate and
`acetyl chloride dissolved in ethanol is a granular precipitate
`consisting of the creatine hydrochloride salt in high purity
`and yield. Yield is measured by 1H-NMR analysis used for
`organic chemicals. 1H-NMR uses spectroscopy and nuclear
`magnetic resonance technology to ascertain the structure of
`chemical compounds.
`The reactants are measured as mole equivalents While the
`solvent is measured as milliliters per gram of creatine hydro
`chloride salt. The preferred process uses 1 .4 mole equivalents
`of acetyl chloride. Above 1.5 and including 2.0 mole equiva
`lents acetyl chloride, the process produces less desirable cre
`atine ethyl ester hydrochloride at a sacri?ce of yield for cre
`atine hydrochloride. Above 2.0 mole equivalents acetyl
`chloride, the process forms creatinine hydrochloride. The
`preferred process dissolves the reactants in 10 ml of ethanol.
`Alternatively, the process has ethanol ranging from about 6 to
`about 10 ml. The preferred process operates in a temperature
`range of 25 deg. C. to 35 deg. C. At temperatures above the
`preferred range including 50 deg. C., the process produces the
`less desirable creatine ethyl ester hydrochloride. In excess of
`50 deg. C., the process produces creatinine hydrochloride.
`
`Vireo Systems, Inc. Ex. 2009 - 002
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947
`
`

`
`US 7,608,641 B2
`
`3
`However, even in the preferred embodiment minor fractions
`of creatine ethyl ester hydrochloride and creatinine hydro
`chloride are produced.
`To form creatine hydrochloride salt, a manufacturer blends
`creatine monohydrate With acetyl chloride in a vessel. Then
`ethanol is added to the vessel as a solvent. The temperature of
`the solution is raised to betWeen about 24 deg. C. to about 50
`deg. C., preferably to 25 deg. C. In that condition, the solution
`precipitates a hydrochloride salt of creatine in granular form
`in the vessel. After reducing the temperature and pressure to
`ambient atmospheric temperature and pressure, the manufac
`turer collects the granules of creatine hydrochloride salt then
`packages the granules for consumption by humans or live
`stock.
`As an alternative method, a manufacturer produces creat
`ine hydrochloride by bubbling gaseous HCl into diethyl ether
`solvent. Then, creatine monohydrate is stirred into the sol
`vent. From the reaction, creatine hydrochloride precipitates.
`The manufacturer then ?lters and Washes the precipitate.
`Lastly, the precipitate dries at room temperature to a crystal
`line form, White in color and then is packaged for human or
`livestock consumption. In using the alternative method, the
`HCl may have a range of concentrations so long as the HCl
`exceeds the molar equivalent of creatine monohydrate. Next,
`the alternative method stirred from about 0 grams to about 5
`grams of creatine monohydrate into the solution at 25 deg. C.
`for tWo hours. Filtering and Washing Were performed With 50
`milliliters of fresh diethyl ether.
`Variations or modi?cations to the subj ect matter may occur
`to those skilled in the art upon revieW of the invention as
`described herein. Such variations, if Within the spirit of this
`development, are intended to be encompassed Within the
`scope of the invention as de?ned herein. The description of
`the preferred embodiment, as provided, is set forth for illus
`trative purposes only.
`We claim:
`1. A supplement to increase muscle mass and muscle per
`formance consisting of creatine hydrochloride salt formed
`from the reaction product of:
`
`5
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`20
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`25
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`30
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`4
`about 0.8 to about 1.2 mole equivalent creatine monohy
`drate; and
`about 1.1 to about 1.4 mole equivalents acetyl chloride,
`dissolved in about 6 to about 10 milliliters alcohol solution
`per gram of creatine hydrochloride salt at a temperature
`of about 25° C. to about 35° C.,
`Wherein the supplement has an aqueous solubility of at
`least 150 mg/ml.
`2. The supplement of claim 1, Wherein the reaction product
`is formed from:
`about 1 mole equivalent creatine monohydrate; and
`about 1.4 mole equivalents acetyl chloride dissolved in
`about 10 milliliters ethanol solution.
`3. The supplement of claim 2, Wherein the supplement is
`precipitated as granules and then packaged into an oral dos
`age form.
`4. The supplement of claim 1, Wherein the supplement has
`an aqueous solubility of at least an order of magnitude higher
`than the aqueous solubility of creatine monohydrate.
`5. The supplement of claim 1, Wherein the yield of creatine
`hydrochloride salt is approximately 94 percent.
`6. A supplement for to increase muscle mass and muscle
`performance consisting of creatine hydrochloride salt formed
`from the reaction product of:
`about 1 mole equivalent creatine monohydrate:
`about 1.4 mole equivalents acetyl chloride;
`said creatine monohydrate and said acetyl chloride dissolv
`ing in about 10 milliliters ethanol solution at a tempera
`ture of about 250 C. forming a solution of creatine hydro
`chloride having an aqueous solubility of at least 150
`mg/ml; and
`thus precipitating granules of creatine hydrochloride salt
`from the solution for oral dosage as one pill, capsule,
`tablet, or liquid.
`7. The supplement of claim 6, Wherein the yield of creatine
`hydrochloride salt is approximately 94 percent.
`
`*
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`*
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`*
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`*
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`*
`
`Vireo Systems, Inc. Ex. 2009 - 003
`
`
`Harvest Trading Group, Inc. v. Vireo Systems, Inc.
`IPR2016-00947