The present invention provides methods for preparation of metallic amino acid chelates that are electrically neutral and free of interfering ions, by reacting a metal carbonate and an acidic amino acid in an aqueous solution, and the uses of said metallic amino acid chelates. The metallic amino acid chelates can be added to a product such as medical supplies, foods, beverages, cosmetics, feeds, etc., with maintaining the stability of the product at a variety of temperature and pH ranges and also having no effect on the properties of the product, including taste and appearance.

Description of the Invention

SUMMARY OF THE INVENTION

Accordingly, the object of the present invention is to solve the aforementioned problems encountered in the prior art.

That is, an object of the present invention is to provide a method for preparation of amino acid chelates by a novel process of reacting a naturally occurring or synthetic metal carbonate with an amino acid in an aqueous solution. According to this method, a variety of amino acid chelates that are electrically neutral and free of interfering ions can easily be prepared without the production of byproducts.

Another object of the present invention is to provide a method for preparation of amino acid chelates by additionally reacting a metal sulfate during or after the above reaction procedure, wherein the amino acid chelate comprises a metal ion derived from the metal sulfate and simultaneously different from a metal ion of the metal carbonate.

Still another object of the present invention is to provide a variety of amino acid chelates obtained from the above methods.

Still yet another object of the present invention is to provide compositions containing the above amino acid chelates as an active ingredient in a therapeutically effective amount, a sitologically effective amount or a cosmetically effective amount. These compositions can be used for formulations of drugs, foods, beverages, cosmetics and the like depending upon the uses thereof.

To accomplish the foregoing objects and advantages, the present invention provides a method comprising the step of reacting a naturally occurring or synthetic metal carbonate with an acidic amino acid in an aqueous solution to produce amino acid chelates.

A metal carbonate useful for the preparation method according to the present invention is not particularly limited and includes carbonates of metals with a valence of 2 or more such as calcium, copper, zinc, iron, chromium, cobalt, manganese, magnesium, etc. Exemplary metal carbonates include calcium carbonate, copper carbonate, zinc carbonate, ferrous carbonate, cobalt carbonate, chromium carbonate, magnesium carbonate, manganese carbonate, etc. In some embodiments, a combination of two or more metal carbonates as described above may be used.

The metal carbonate to be used in the present invention may be naturally occurring metal carbonates, synthetic metal carbonates, or a combination thereof. Particularly, the naturally occurring metal carbonates are more preferable because they contain a variety of minerals.

Calcium carbonate, one of metal carbonates useful for the preparation method of the present invention, is briefly discussed herein below.

At present, naturally occurring or synthetic calcium carbonates are applied to many uses and representative examples thereof are their use as additives for calcium-containing foods such as milk, beverages, cookies, snacks and the like. However, calcium being in the form of calcium carbonate is dispersed in water but not completely dissolved, whereby it cannot be applied to the preparation of clear foods such as beverages. Moreover, it tends to be precipitated with the lapse of time, thereby the water-dispersed form has limited applications to many foods.

While naturally-occurring calcium carbonates have a merit of containing a variety of minerals as stated previously, they simultaneously have demerits of a low solubility and low absorptivity in vivo owing to their inorganic properties.

The naturally occurring calcium carbonates are contained, for example, in eggshell calcium, cuttlebone calcium, shell calcium (originated from shells of clam, oyster, etc), seaweed calcium, etc. Of these, the seaweed calcium is a calcium source obtained from calcified seaweeds (phymatolithon calcareum known as "lithothannion") and contains calcium carbonate and magnesium carbonate as major components. The components of seaweed calcium and whey calcium are listed in TABLE 1 (see Original Patent) as below, respectively, wherein the whey calcium is present in milk and comprises calcium phosphate but not calcium carbonate.

As seen in TABLE 1 as above, the seaweed calcium contains magnesium and calcium at a ratio of approximately 1:10 (magnesium:calcium) and little phosphorous. Differently from general calcium stocks including synthetic calcium carbonate, the seaweed calcium contains a variety of minerals which promote the physiological function of calcium. However, even when such naturally occurring calcium carbonates are employed as a calcium source, the problem of insolubility cannot be solved, as stated previously, thereby restricting the extension of uses thereof. Meanwhile, when calcium carbonates contained therein are converted to metallic amino acid chelates like in the present invention, a high absorption rate in vivo can be achieved due to the solubility of the chelate per se, which is proved by EXAMPLES as will be illustrated later herein.

Acidic amino acids useful for the preparation method according to the present invention are not particularly limited and include, for example, glutamic acid, aspartic acid, etc. In some embodiments, a combination of two or more amino acids may be employed.

The amount of metal carbonate and acidic amino acid used in the reaction can be determined depending upon various parameters such as the valence of metal, the reactivity of salt, the reactivity of amino acid, etc., and is preferably in the range of a molar ratio of 1:1.about.1:4 (metal carbonate:acidic amino acid).

The reaction for synthesis of the amino acid chelate where a metal ion with a valence of 2 is used as the metal carbonate can be illustrated in REACTION FORMULA 1 as below.

Reaction Formula 1 XCO.sub.3+2H(AA).fwdarw.X(AA).sub.2+CO.sub.2+H.sub.2O wherein, X is a divalent metal ion and AA is an amino acid.

The reaction for synthesis of the amino acid chelate where a metal ion with a valence of 3 is used as the metal carbonate can be illustrated in REACTION FORMULA 2 as below.

Reaction Formula 2 X'.sub.2(CO.sub.3).sub.3+6H(AA).fwdarw.2X'(AA).sub.3+3CO.sub.2+3H.sub.2O wherein, X' is a trivalent metal ion and AA is an amino acid.

As can be seen in these reaction formulas, according to the preparation method of the present invention, sulfuric acid as a reaction inhibitor is not created, and the generated byproducts do not affect a desired product and reaction procedure because they are volatile carbon dioxide and water, and the desired product can readily be separated, and the resulting product is electrically neutral.

In the preparation method of the present invention, the reaction of metal carbonate and acidic amino acid is performed in an aqueous solution, wherein water is desirably used as a medium for the aqueous solution, but is not particularly limited thereto so long as the reaction medium does not affect the reaction mechanism and can easily be separated from the product Furthermore, other known materials for increasing the rate and efficiency of reaction may be added to the water or other reaction medium.

The temperature of reaction is preferably in the range of 0.about.100.degree. C. and if the temperature is excessively low, the reactivity becomes low, whereas if the temperature is excessively high, energy is wasted and deterioration of some amino acids can occur.

The pH of reaction is preferably adjusted to 4.about.7 to ensure the smooth progress of the reaction and to maintain neutrality, and more preferably to 4.5.about.6.5.

In some embodiments, a metal sulfate may be added to a reaction system where a metal carbonate is reacted with an acidic amino acid in an aqueous solution, as described above, when the reaction is initiated, or during the reaction, or after completion of the reaction In order to prevent direct reaction of the metal sulfate and the amino acid, the metal sulfate is preferably added during the reaction, and more preferably after completion of the reaction.

The metal sulfate useful for the preparation method according to the present invention includes, for example, but is not limited to calcium sulfate, magnesium sulfate, zinc sulfate, copper sulfate, ferrous sulfate, manganese sulfate, chromium sulfate, cobalt sulfate, etc.

The amount of metal sulfate additionally added to the reaction is desirably at a molar ratio of 1:1.about.1:4 (metal sulfate:amino acid chelate derived from metal carbonate).

The temperature and pH in the additional reaction of metal sulfate are the same as or very similar to those of the reaction of metal carbonate, as described previously.

Where a metal ion (X) in a metal carbonate salt has a valence of 2 as in REACTION FORMULA 1 and a metal sulfate comprising a metal ion (M) with a valence of 2 other an the metal ion (X) is employed, this additional reaction is as illustrated in REACTION FORMULA 3, blow.

Reaction Formula 3 XCO.sub.3+2H(AA)+MSO.sub.4.fwdarw.M(AA).sub.2+CO.sub.2+H.sub.2O+XSO.sub.4 wherein, X is a divalent metal ion, and M is a divalent metal ion other than X, and AA is an amino acid.

Where a metal sulfate of a metal ion (M') with a valence of 3 is employed, this additional reaction is as illustrated in REACTION FORMULA 4, below.

Reaction Formula 4 3XCO.sub.3+6H(AA)+M'.sub.2(SO.sub.4).sub.3.fwdarw.2(M'(AA).sub.3)+3CO.sub- .2+3H.sub.2O+3XSO.sub.4 wherein, X is a divalent metal ion, and M' is a trivalent metal ion, and AA is an amino acid.

Where a metal carbonate and metal sulfate are subsequently reacted, in other words, the metal carbonate first reacts with an acidic amino acid and then the metal sulfate reacts with a resulting product, an amino acid chelate based upon the metal carbonate is converted to an amino chelate based upon the metal sulfate. Such subsequent reaction is illustrated, for instance, in REACTION FORMULA 5 as below.

Reaction Formula 5 XCO.sub.3+2H(AA).fwdarw.X(AA).sub.2+CO.sub.2+H.sub.2O (1) X(AA).sub.2+MSO.sub.4.fwdarw.M(AA).sub.2+XSO.sub.4 (2) wherein, X is a divalent metal ion, and M is a divalent metal ion other than X, and AA is an amino acid.

Preferably, the metal carbonate is calcium carbonate and the metal sulfate is a metal sulfate of a metal ion with a valence of 2 other than calcium ion. Accordingly, where the metal carbonate is calcium carbonate and the metal sulfate comprises a divalent metal ion and the calcium amino acid chelate is subsequently reacted with metal sulfate, the reaction is illustrated in REACTION FORMULA 6 as below.

Reaction Formula 6 CaCO.sub.3+2H(AA).fwdarw.Ca(AA).sub.2+CO.sub.2+H.sub.2O (1) Ca(AA).sub.2+MSO.sub.4.fwdarw.M(AA).sub.2+CaSO.sub.4.dwnarw. (2) wherein, M is a divalent metal ion other than calcium ion, and AA is an amino acid.

Further, where calcium carbonate and a metal sulfate with a valence of 2 simultaneously react with an amino acid, such a reaction is illustrated in REACTION FORMULA 7 as below.

Reaction Formula 7 3CaCO.sub.3+6H(AA)+M'.sub.2(SO.sub.4).sub.3.fwdarw.2(M'(AA).sub.3)+3CO.su- b.2+3H.sub.2O+3CaSO.sub.4 wherein, M' is a trivalent metal ion, and AA is an amino acid.

In the above reaction formulae, calcium sulfate can easily be separated from a reaction mixture containing other metal sulfates.

As can be seen from the description so far, an amino acid chelate containing a metal (M) other than calcium can be made by a direct method of reacting the carbonate of the metal (M) with an amino acid, or by an indirect method of synthesizing a calcium amino acid chelate and subsequently reacting the sulfate of the metal (M) with the calcium amino acid chelate, wherein the latter, i.e., the indirect method is more desirable in view of reactivity, easy separation of byproducts, etc., in spite of being a relatively more complicated procedure.

The present invention also provides amino acid chelates as represented in FORMULAS 1 and 2 as below, respectively, which are prepared by the above methods.

Formula 1 M(AA).sub.2 wherein, M is a divalent metal ion, and AA is an amino acid. Formula 2 M'(AA).sub.3 wherein, M' is a trivalent metal ion, and AA is an amino acid.

Amino acid mineral chelates which can be prepared by methods according to the present invention include, for example, but are not limited to calcium glutamate/aspartate, calcium bisglutamate, calcium bisasparate, copper glutamate/aspartate, copper bisglutamate, copper bisaspartate, zinc glutarate/aspartate, zinc bisglutamate, zinc bisaspartate, iron glutamate/aspartate, iron bisglutamate, iron bisaspartate, iron bisglutamate/aspartate, iron glutamate/bisaspartate, chromium glutamate/aspartate, chromium bisglutamate, chromium bisaspartate, chromium bisglutamate/aspartate, chromium glutamate/bisaspartate, cobalt glutamate/aspartate, cobalt bisglutamate, cobalt bisaspartate, magnesium glutamate/aspartate, magnesium bisglutamate, magnesium bisaspartate, manganese glutamate/aspartate, manganese bisglutamate, manganese bisaspartate, or a mixture of two or more of these materials.

The present invention also provides compositions containing amino acid chelates of FORMULAS 1 and/or 2 as an active ingredient at a therapeutically effective amount, a sitologically effective amount or a cosmetically effective amount.

The amino acid chelates of FORMULAS 1 and 2 can be formulated to various dosage forms of pharmaceutical composition depending upon their intended use. More specifically, in preparation of a pharmaceutical composition according to the present invention, the amino acid chelates of FORMULAS 1 and/or 2 as active ingredients can be mixed with a pharmaceutically acceptable carrier, including diluents, excipients, etc., depending upon a required formulation. For example, the pharmaceutical composition according to the present invention can be formulated to drugs for oral or injection administration.

The amino acid chelates of FORMULAS 1 and 2 as active ingredients can be formulated to one dosage unit or multi-dosage unit by known techniques using pharmaceutically acceptable excipients. Drugs may be prepared in the form of solution, suspension or emulsion in an oil or aqueous medium and may contain conventional suspending agent, emulsifying agent or stabilizer. Furthermore, drugs may be prepared in the form of dry powder which will be dissolved in sterile water free of pyrogen prior to use thereof. The amino acid chelates of FORMULAS 1 and 2 may also be formulated to suppository using conventional suppository agents such as cocoa butter or glycerides. Solid drugs for oral administration can be made in the form of capsules, tablets, pills, powders, etc. in which the tablets and pills are particularly useful. The solid drugs can be manufactured by mixing the amino acid chelates of FORMULAS 1 and/or 2 with one or more inactive diluents such as sucrose, lactose, starch or the like, a lubricant such as magnesium stearate, other carriers such as disintegrating agent or coupling agent, etc.

If necessary, the amino acid chelates of FORMULAS 1 and/or 2 or a composition containing them as an active ingredient may be administered together with other drugs.

The term "therapeutically effective amount" as used herein refers to that amount of the compound being administered which will prevent, alleviate or ameliorate to some extent one or more of the symptoms of the disorder being treated. The therapeutically effective amount can be experientially determined by use of well-known in vivo and in vitro model systems pertaining to the disorders being treated.

In the case of formulation as one dosage unit, the amino acid chelates of FORMULAS 1 and/or 2 as active ingredients are preferably contained at an amount of 0.1.about.1000 mg per dose. The administration on amount of drug can be determined by a physician in consideration of the weight, age, disease state and the like of a patient. The administration amount necessary for treatment of an adult is generally about 1.about.1000 mg per day depending upon the frequency and intensity of administration. On muscular or vascular administration, about 1.about.500 mg per day is sufficient for an average adult male but a larger amount may be preferable for some patients.

The term "sitologically effective amount" as used herein refers to the amount of the active ingredient which is useful to improve the metabolic functioning of a patient and also which does not cause any adverse side effects.

The term "cosmetically effective amount" as used herein refers to the amount of the active ingredient which is effective to improve the beauty-related conditions such as skin condition, hair condition, etc. and also which does not does not cause any adverse side effects.

The sitologically effective amount and cosmetically effective amount can be determined by a variety of parameters such as uses and properties of the composition, thus they are not particularly limited.

As a result, the compositions according to the present invention can be applied to various uses including, for example, a pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable carrier, a food or beverage composition comprising an active ingredient and a sitologically acceptable carrier; and a cosmetics composition comprising an active ingredient and a cosmetically acceptable carrier, in which the active ingredients are the compounds of FORMULAS 1 and/or 2, respectively.
 

Claim 1 of 13 Claims

1. A method for preparation of an amino acid chelates, comprising the step of reacting a naturally occurring or synthetic metal carbonate with an acidic amino acid in an aqueous solution, wherein the metal carbonate is one or more carbonates with a valence of 2 or more selected from the group consisting of calcium carbonate, copper carbonate, zinc carbonate, ferrous carbonate, cobalt carbonate, chromium carbonate, magnesium carbonate and manganese carbonate; and the acidic amino acid is glutamic acid, aspartic acid or a combination thereof.
 

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