Magnesium taurate and other mineral taurates

A magnesium-taurine compound and its method of synthesis. the compound is synthesized by reacting taurine and magnesium in a 2:1 molar ratio. The resulting mixture is diluted with methanol and the remaining clear filtrate is crystallized from methanol. This compound may be administered orally as a nutritional supplement or may be administered orally or intravenously for the therapeutic or prophylactic treatment of acute cardiac conditions.

FIELD OF THE INVENTION 
The present invention relates to the synthesis and use of complexes 
comprising biologically available mineral taurates. More specifically, the 
invention relates to the synthesis of magnesium taurate and its use as a 
nutritional supplement and therapeutic agent. 
BACKGROUND OF THE INVENTION 
Magnesium is nutritionally important for maintenance of vascular integrity, 
but is often deficient in fatty, refined modern diets (Seelig et al., Am. 
J. Clin. Nutr., 27:59-79, 1974). Deleterious vascular effects of magnesium 
deficiency include cardiac arrhythmias and hypertension (Anderson et al., 
Can. Med. Assoc. J., 113:199-203, 1975). Magnesium supplements have been 
shown to reduce such hypertension (Dyckner et al., Brit. Med. J., 
286:1847-1849, 1983; Motoyama et al., Hypertension, 113:227-232, 1989; 
Ryan et al., Ann. Clin. Res., 16:81-88, 1984). Intravenous administration 
of magnesium salts in the treatment of acute myocardial infarction has 
been found to decrease the subsequent incidence of arrhythmias and to 
improve survival. Intravenous magnesium also exerts a therapeutic effect 
in hypertensive crises and intractable arrhythmias (Ryan et al., 1984; 
Iseri, Drugs, 16:81-88, 1984; Shechter et al., Arch. Intern, Med., 
152:2189-2196, 1992). 
Intracellular magnesium, usually in complex with ATP, is an essential 
cofactor, usually in a complex with ATP, for numerous enzymes including 
energy-dependent membrane transport proteins such as the sodium/potassium 
ATPase and the calcium ATPase (Altura et al., Drugs, 28(Suppl. 1):120-142, 
1984. Significant intracellular magnesium deficiency impairs the activity 
of these transporters, resulting in decreased intracellular levels of 
potassium, and increased intracellular levels of sodium and calcium. 
Taurine is an amino acid present in high concentrations in excitable and 
secretory tissue. Its role in cardiac function has received particular 
attention (Huxtable, Physiol. Rev., 72:101-163, 1992; Schaffer et al., 
Taurine in Health and Disease, pp. 171-180, 1994). Although taurine can be 
synthesized endogenously from the amino acid cysteine, in mammals it is 
derived principally from the diet and is thus considered a "conditionally 
essential" nutrient. Conventional diets supply 40-400 mg of taurine daily, 
while vegetarian diets are extremely low in this amino acid (Huxtable, 
1992). 
The main function of taurine in mammals appears to be the regulation of 
transmembrane ionic movements, especially the regulation of calcium 
distribution (Schaffer et al., 1994; Huxtable, 1992; Schaffer et al., 
Taurine: Functional Neurochemistry, Physiology and Cardiology, pp. 
217-225, 1990). However, the mechanisms of this regulation are not well 
understood. Taurine also exerts an anti-atherogenic action in animal 
models of atherosclerosis or arterial calcinosis (Petty et al., Eur. J. 
Pharmacol., 180:119-127, 1990; Yamauchi-Takihara et al., Biochem. Biophys. 
Res. Commun., 140:679-683, 1986). Taurine has also been shown to moderate 
blood pressure increases and thus may have a clinical antihypertensive 
effect. 
Taurine exerts a platelet stabilizing effect both in vitro and, after oral 
administration, ex vivo (Hayes et al., Am. J. Clin. Nutr., 49:1211-1216, 
1989; Atahanov, Arzneim-Forsch/Drug Res., 42:1311-1313, 1992). Acute 
intravenous administration of taurine reduces the incidence of arrhythmias 
in animals treated with arrhythmogenic agents and multi-gram doses have 
been shown to be effective in the treatment of ischemic congestive heart 
failure (Azuma et al., Curr. Ther. Res., 34:543-557, 1983). Thus, 
increased taurine intake appears to be beneficial to vascular health. 
To insure optimal magnesium status, magnesium supplements are frequently 
advisable. Magnesium supplements are especially important for diabetics, 
as these individuals typically display reduced intracellular, plasma and 
bone levels of magnesium. Magnesium oxide is commonly used as a dietary 
supplement, although the bioavailability of the magnesium in this salt is 
far from optimal. Soluble magnesium salt complexes with good nutritional 
availability, including citrate and glycinate, typically are low in 
magnesium, the majority of the complex consisting of the counteranion 
which has no nutritional utility. There is a need in the art for a 
magnesium supplement in which the magnesium is complexed with a 
counteranion which itself has nutritional utility and would complement the 
vascular-protective actions of magnesium. The present invention addresses 
this need. 
SUMMARY OF THE INVENTION 
The present invention provides a compound having the formula (H.sub.2 
N--CH.sub.2 --CH.sub.2 --SO.sub.3.sup.-).sub.2 X.sup.2+, wherein X is a 
divalent metal cation. Preferably, X is calcium or zinc; most preferably, 
X is magnesium. 
Another embodiment of the invention is a method for providing a divalent 
mineral nutrient to a mammal, comprising orally administering to the 
mammal a divalent mineral taurate. Preferably, the divalent metal cation 
is magnesium. The magnesium taurate may be in the form of a salt or a 
complex. The divalent metal cation may also be calcium or zinc. The 
compound is advantageously administered in a daily dosage of between about 
2 grams and about 7 grams; however the most preferred daily dosage is 
about 4.5 grams. According to a further aspect of this embodiment, the 
nutrient is administered in the form of a tablet or capsule. 
The present invention also provides a method of treating an acute or 
chronic cardiac condition in a patient comprising parenterally 
administering to the patient an effective therapeutic amount of magnesium 
taurate. Advantageously, the compound is administered intravenously and 
the acute cardiac condition is myocardial infarction. According to another 
aspect of this embodiment, the effective therapeutic dosage is between 
about 200 mg/hour and about 1500 mg/hour; most preferably, it is between 
about 500 mg/hour and about 1000 mg/hour. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention provides a magnesium taurate salt and a magnesium 
taurate complex for the nutritional and therapeutic administration of 
magnesium and taurine, both of which are beneficial to vascular health. 
The reaction of taurine with magnesium oxide, magnesium hydroxide or 
magnesium salts, under appropriate conditions, yields products containing 
magnesium and taurine. Under alkaline conditions, taurine has a net 
negative charge and may form both a salt and a complex with magnesium in 
which two molecules of taurine associate with one atom of magnesium as 
depicted below. 
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SALT COMPLEX 
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These compounds may be used both as a source of the essential nutrient 
magnesium and as a source of the conditionally essential amino acid 
taurine. The oral administration of these compounds delivers magnesium and 
taurine to appropriate sites of action. The magnesium-taurine compounds 
are also useful as therapeutic agents for congestive heart failure, acute 
myocardial infarction or other acute cardiac conditions associated with an 
increased risk for arrhythmias or congestive failure, as well as chronic 
disorders including essential hypertension, diabetes, insulin resistance 
syndrome and bronchospasm. Thus, the administration of magnesium taurate 
may have prophylactic as well as therapeutic applications. 
The magnesium taurate salt of the invention is highly soluble in water and 
provides good nutritional availability of both magnesium and taurine. The 
complex form is insoluble in water, but will slowly dissolve in water as a 
result of its conversion to the salt form. The complex and salt forms are 
thus interchangeable. The dissolution of the complex form in water is 
greatly accelerated in the presence of acid. 
The acute anti-arrhythmic effect of both magnesium and taurine, as well as 
taurine's ability to control congestive heart failure, suggests that this 
complex is of particular benefit in the management of acute ischemic 
cardiac episodes when administered intravenously. A daily dose providing 
the full U.S. recommended daily allowance (RDA) of magnesium (400 mg) 
would concurrently provide about 4.1 g taurine--well within the range 
demonstrated to be therapeutically effective in congestive heart failure. 
The magnesium taurate protocol is described in Example 1. Magnesium 
hydroxide and taurine are mixed and heated in water. Most of the water is 
removed by evaporation, and then alcohol is added to precipitate the 
product and allow it to be separated by filtration. 
Since two taurine molecules combine with one magnesium atom, it is 
preferred that the molar ratio of taurine to magnesium be about 2:1, 
although ratios of between about 1.5:1 and about 2.5:1 are contemplated. 
NMR analysis confirms the presence of taurine in the product. The product 
is extremely water-soluble. Surprisingly, the product is also stable to 
precipitation in the presence of additional alkali or in the presence of 
additional carbonate, thus illustrating the unexpected stability of this 
magnesium-containing compound. 
For oral administration as a nutritional supplement, the compound may be 
provided as a tablet, aqueous or oil suspension, dispersible powder or 
granule, emulsion, hard or soft capsule, syrup or elixir. Compositions 
intended for oral use may be prepared according to any method known in the 
art for the manufacture of pharmaceutical compositions and such 
compositions may contain one or more of the following agents: sweeteners, 
flavoring agents, coloring agents and preservatives. The sweetening and 
flavoring agents will increase the palatability of the preparation. 
Tablets containing the magnesium taurate in admixture with non-toxic 
pharmaceutically acceptable excipients suitable for tablet manufacture are 
acceptable. Such excipients include inert diluents such as calcium 
carbonate, sodium carbonate, lactose, calcium phosphate or sodium 
phosphate; granulating and disintegrating agents, such as corn starch or 
alginic acid; binding agents such as starch, gelatin or acacia; and 
lubricating agents such as magnesium stearate, stearic acid or talc. 
Tablets may be uncoated or may be coated by known techniques to delay 
disintegration and absorption in the gastrointestinal tract and thereby 
provide a sustained action over a longer period of time. For example, a 
time delay material such as glyceryl monostearate or glyceryl distearate 
alone or with a wax may be employed. 
Formulations for oral use may also be presented as hard gelatin capsules 
wherein the active ingredient is mixed with an inert solid diluent, for 
example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin 
capsules wherein the active ingredient is mixed with water or an oil 
medium, such as peanut oil, liquid paraffin or olive oil. 
Aqueous suspensions may contain the magnesium taurate complex of the 
invention in admixture with excipients suitable for the manufacture of 
aqueous suspensions. Such excipients include suspending agents, dispersing 
or wetting agents, one or more preservatives, one or more coloring agents, 
one or more flavoring agents and one or more sweetening agents such as 
sucrose or saccharin. 
Oil suspensions may be formulated by suspending the active ingredient in a 
vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, 
or in a mineral oil such as liquid paraffin. The oil suspension may 
contain a thickening agent, such as beeswax, hard paraffin or cetyl 
alcohol. Sweetening agents, such as those set forth above, and flavoring 
agents may be added to provide a palatable oral preparation. These 
compositions may be preserved by an added antioxidant such as ascorbic 
acid. Dispersible powders and granules of the invention suitable for 
preparation of an aqueous suspension by the addition of water provide the 
active ingredient in admixture with a dispersing or wetting agent, a 
suspending agent, and one or more preservatives. Additional excipients, 
for example sweetening, flavoring and coloring agents, may also be 
present. 
Syrups and elixirs may be formulated with sweetening agents, such as 
glycerol, sorbitol or sucrose. Such formulations may also contain a 
demulcent, a preservative, a flavoring or a coloring agent. 
The magnesium taurate preparations for parenteral administration may be in 
the form of a sterile injectable preparation, such as a sterile injectable 
aqueous or oleaginous suspension. This suspension may be formulated 
according to methods well known in the art using suitable dispersing or 
wetting agents and suspending agents. The sterile injectable preparation 
may also be a sterile injectable solution or suspension in a non-toxic 
parenterally-acceptable diluent or solvent, such as a solution in 
1,3-butanediol. Suitable diluents include, for example, water, Ringer's 
solution and isotonic sodium chloride solution. In addition, sterile fixed 
oils may be employed conventionally as a solvent or suspending medium. For 
this purpose, any bland fixed oil may be employed including synthetic mono 
or diglycerides. In addition, fatty acids such as oleic acid may likewise 
be used in the preparation of injectable preparations. 
The pharmaceutical compositions may also be in the form of oil-in-water 
emulsions. The oily phase may be a vegetable oil, such as olive oil or 
arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof. 
Suitable emulsifying agents include naturally-occurring gums such as gum 
acacia and gum tragacanth, naturally occurring phosphatides, such as 
soybean lecithin, esters or partial esters derived from fatty acids and 
hexitol anhydrides, such as sorbitan mono-oleate, and condensation 
products of these partial esters with ethylene oxide, such as 
polyoxyethylene sorbitan mono-oleate. The emulsions may also contain 
sweetening and flavoring agents. 
In a preferred embodiment, the amount of the complex administered orally is 
between about 2 g and about 7 g daily, corresponding to between 
approximately 200 mg and 600 mg magnesium, the remainder being taurine. In 
a particularly preferred embodiment, the amount of the complex 
administered daily is about 4 g, corresponding to about 400 mg magnesium. 
The preferred administration schedule for delivery of 400 mg magnesium 
would be two tablets, twice daily; if one were to ingest another 
high-availability source of magnesium plus straight taurine to achieve 
analogous benefits, eight tablets daily would be needed which is hardly 
optimal from a compliance standpoint. 
For therapeutic or prophylactic use in myocardial infarction or other acute 
cardiac condition, the magnesium taurate complex is solubilized in an 
aqueous saline solution and administered parenterally. Although various 
administration routes including, for example, intramuscular, subcutaneous, 
intraperitoneal and intraarterial are contemplated, the preferred route is 
intravenous administration. The amount administered will depend on the 
weight of the patient and the severity of the condition, although 
contemplated doses for such administration will typically be from about 
200 mg/hr to about 1500 mg/hr for a time sufficient to result in 
improvement of the condition. In a particularly preferred embodiment, this 
amount is between about 500 mg/hr and about 1000 mg/hr. Alternatively, the 
magnesium taurate may be administered in a bolus dose over a shorter 
period of time. Such dose is preferably greater than 5 grams once per day. 
Although the synthesis and use of magnesium taurate is described herein, it 
is evident that other divalent mineral nutrients may also be complexed 
with taurine for oral administration as a nutritional supplement or for 
intravenous or oral administration as a therapeutic or prophylactic agent. 
Such essential nutrients include, for example, calcium and zinc, although 
other nutrients are also within the scope of the invention. Calcium is 
essential for preservation of bone density and in lowering blood pressure 
in some individuals, while zinc promotes efficient cell growth, wound 
healing, effective immune function and membrane stabilization. 
The RDA for calcium is about 800 mg per day and that for zinc is about 15 
mg per day. It is not required that the calcium taurate complex provide 
the entire daily amount of calcium as this will require about 10 g of 
taurine, but could be used to provide a portion of the RDA. The zinc RDA 
could be provided by a zinc taurate complex containing about 15 mg of zinc 
and about 200 mg taurine. 
It is also evident that many variations of the synthetic scheme described 
below may be used to generate the compounds of the present invention. Any 
such scheme resulting in production of a divalent cation-taurine complex 
is within the scope of the present invention.

EXAMPLE 1 
SYNTHESIS OF MAGNESIUM TAURATE 
A mixture of magnesium hydroxide (9.50 g, 8.62 mmol) and taurine (2.16 g, 
17.2 mmol) in 20 ml water was refluxed for 7 hours, then evaporated under 
vacuum to remove most of the water. The paste was diluted with 10 ml 
ethanol, and after two hours the solid was collected by filtration and 
dried. Magnesium taurate was obtained as a white powder (about 99% yield). 
Magnesium taurate could also be obtained as a white powder by 
lyophilization or by further drying of the paste remaining after 
evaporation of the reaction mixture. 
Magnesium taurate obtained by this reaction scheme is a variable mixture of 
the complex form and the salt form. The salt form rapidly dissolves in 
water, leaving behind a solid that is primarily the complex form. The 
complex form dissolves more slowly in water as it converts to the salt 
form. 
Preparation of magnesium taurate salt is described in the following 
example. 
EXAMPLE 2 
SYNTHESIS OF MAGNESIUM TAURATE SALT 
Magnesium turnings (96.0 mg, 4 mmol; Aldrich, St. Louis, Mo.) were stirred 
in 10 ml methanol until completely reacted and dissolved. The excess 
methanol was evaporated, leaving solid magnesium methoxide. To the solid 
magnesium methoxide was added a solution of taurine (1 g, 8 mmol; Aldrich) 
in water (10 ml). The reaction mixture was vigorously stirred to form a 
clear solution, then heated to boiling and refluxed for 10-15 minutes. The 
solution was allowed to cool to room temperature, resulting in a milky 
colloidal solution which was then evaporated to dryness under vacuum to 
produce a white solid. Water (10 ml) and then methanol (20 ml) were then 
added to the resulting residue. After 2-3 hours with occasional shaking, 
the remaining undissolved white solids were removed by filtration. This 
material (about 50% yield) consisted of a small amount of taurine and 
magnesium salts, and an amorphous form of the magnesium taurate complex. 
The clear filtrate was evaporated to a wet paste which was slowly diluted 
with methanol (about 10 ml) until crystallization appeared complete. The 
yield of crystalline magnesium taurate was about 50% (about 0.45-0.60 g). 
The melting point (decomposition) was about 300.degree.. 
To verify the proposed structure of the resulting magnesium taurate salt, 
an elemental analysis was performed as follows. 
EXAMPLE 3 
ELEMENTAL ANALYSIS 
A sample of the product from Example 1 was analyzed for % C, H, N and S by 
combustion and for % Mg by atomic absorption spectroscopy. The following 
results were obtained. 
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Element value value for dihydrate 
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% C 16.38 15.57 
% H 5.00 5.23 
% N 9.09 9.08 
% S 20.43 20.78 
% Mg 6.25 7.88 
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These results are consistent with a chemical formula of C.sub.4 H.sub.12 
MgN.sub.2 O.sub.6 S.sub.2.2H.sub.2 O and a molecular weight of 308.61. 
This formula and molecular weight are consistent with a 2:1 taurine to 
magnesium ratio as diagrammed hereinabove. The product holds water 
tenaciously, as only 11-12% of the water is lost after 2 hours at 
120.degree. C. 
To further confirm the presence of taurine in the crystalline compound, the 
product of Example 2 was analyzed by proton, carbon, and magnesium 
magnetic resonance spectroscopy as described below. 
EXAMPLE 4 
SPECTROSCOPY STUDIES 
A sample of the salt was dissolved in deuterium oxide and analyzed in a 500 
MHz Brucker Proton Multinuclear Resonance Spectrometer Model AM-500. The 
spectrum showed a symmetrical, closely-spaced multiplet centered at about 
3.11 ppm and an HDO signal at 4.8 ppm. The multiplet is consistent with a 
second-order splitting between the two methylene groups of taurine, both 
of which are shifted downfield relative to the signals of free 
(zwitterionic) taurine (.sup.+ H.sub.3 N--CH.sub.2 CH.sub.2 
SO.sub.3.sup.-) in water. 
Signals due to zwitterionic taurine are undetectable. The protein magnetic 
resonance spectrum of free taurine in deuterium oxide shows two 
symmetrical triplets, centered at 3.49 and 3.32 ppm (coupling constant 
J=6.6), consistent with first-order splitting between the two sets of 
methylene protons. The .sup.13 C spectrum of the salt in deuterium oxide, 
measured in the same instrument (Brucker AM-500), shows signals at 39.71 
ppm (H.sub.2 N--CH.sub.2 --) and at 54.59 ppm (--O.sub.3 S--CH.sub.2). The 
.sup.25 Mg spectrum of the salt in deuterium oxide, measured in the same 
instrument, shows a single signal at exactly the same shift as MgCl.sub.2. 
There is no evidence for the presence of any other magnesium species, such 
as covalent complexes, in the aqueous solution. 
EXAMPLE 5 
ALTERNATIVE SYNTHESIS OF MAGNESIUM TAURATE SALT 
A mixture of magnesium hydroxide (433 mg, 7.46 mmol; Aldrich) and taurine 
(1.87 g, 14.9 mmol) in 20 ml water was heated under reflux for seven 
hours. The resulting milky mixture was allowed to cool, diluted with 40 ml 
methanol and allowed to stand overnight at room temperature. A white 
powder, consisting mostly of magnesium taurate complex, was removed by 
filtration. The clear filtrate was concentrated under vacuum to a pasty 
slurry, then diluted slowly with 10 ml methanol. After 2 hours, 
crystalline magnesium taurate salt was obtained by filtration. The yield 
was 940 mg (41%). The melting point (decomposition) was about 300.degree. 
C. This salt was identical to that obtained in Example 2. 
The magnesium taurate salt when dissolved in water resulted in a clear, 
colorless solution. When a concentrated aqueous solution was heated to 
boiling, the mixture became milky and then formed a fine white precipitate 
of the complex. Upon cooling, the precipitate redissolved, forming a clear 
solution of the salt. 
A dilute suspension of the complex in water has a pH of about 9-10, and 
dissolves slowly to give a clear solution of the salt. The complex 
dissolves more readily if acid is added, and dissolution is very rapid at 
pH values below 5. 
The synthetic scheme for calcium and zinc taurates will be essentially 
similar to Example 5, with the exception that either calcium or zinc 
hydroxide would be reacted with the taurine in the first step of the 
reaction scheme to ultimately form calcium and zinc taurate, respectively. 
The formation of other divalent mineral taurates by variations to the 
synthetic schemes described in Examples 1, 2, and 5, such variations being 
known to the skilled artisan, is also within the scope of the present 
invention. 
The above detailed description of the invention is set forth solely to 
assist in understanding the invention. It is to be understood that 
variations of the invention, including all equivalents now known or later 
developed, are to be considered as falling within the scope of the 
invention, which is limited only by the following claims.