HK1172505B - Slow release magnesium composition and uses thereof - Google Patents

Abstract

The present invention provides compositions that contain magnesium and threonate, or a threonate precursor molecule, formulated for extended or modified release to provide physiological concentrations over a desired time period. The extended release or modified release form is particularly useful in providing Mg to a subject while avoiding adverse side effects such as diarrhea.

Description

Slow-release magnesium composition and use thereof

RELATED APPLICATIONS

Priority of united states provisional application 61/222,420 filed on 7/1/2009, this application claims priority, which is hereby incorporated by reference in its entirety.

Background

Magnesium is the fourth most abundant mineral substance in the human body and plays a variety of roles in keeping the health of the body. At the molecular level, magnesium is a cofactor for three hundred or more enzymes responsible for some of the most important biological activities in mammals, including humans. In living cells, magnesium is also involved in the homeostasis of other minerals (e.g., sodium, potassium, and calcium), as well as the formation, transport, storage, and utilization of Adenosine Triphosphate (ATP), which is the primary energy source for living cells. In humans, magnesium is involved in maintaining normal muscle and nerve function, cardiac rhythm, bone strength, and immune system health. Magnesium is also involved in the regulation of blood glucose levels and in the promotion of normal blood pressure.

Magnesium deficiency is associated with several diseases, including hypertension, atherosclerosis, cardiac arrhythmias, diabetes, and metabolic syndrome. In addition, magnesium deficiency accelerates the cell aging process (Killilea DW, Ames BN. magnesium defect acellular cells senesce in the cut human fibroblasts. Proc Natl Acad Sci U A.2008 Apr 15; 105: 5768-73). Magnesium is also important for brain function. For example, magnesium deficiency is involved in the cause of attention deficit disorder (Kozielec T, Starobrat-Hermelin B. Magnes Res.1997 Jun; 10: 143-8; Mousain-Bosc M, Roche M, Polge A, Pradal-Prat D, Rapin J, Bali JP. Magnes Res.2006 Mar; 19: 46-52), affective disorder (Murk H. Nutritional neuroscience.2002 Dec; 5: 375-89), Alzheimer' S disease (Andrasi E, Pali N, Molnnar Z, Kosel S. JAlzheimers Dis.2005 Aug; 7: 273 AR-84; Cillier AE, Ozturkurk S, Ozt S. Geronology. Nov 8; 53: 419-22; Lemnarville. Geronalog. J. Geronalogy. Nov 8; Pignonex. J. Henschel. 1. Hessi.J. Hessi.32. Hessi. J. Hessi. J. Hessi. Fassi. Hessi.J. Hessi. J. Fassi. J. Hessi. J. Hessi. III, M. J. Hessi. III. J. III, M. III. J. III. Hessi. Miz. III, M. J. Hessi. III, barthelemy C, Garreau B, Lelord G.biol Psychiatry.1985 May; 20: 467-78; pfeiffer SI, Norton J, Nelson L, Shott S.J Austsm Dev Disord.1995 Oct; 25: 481-93; strambi M, Longini M, Hayek J, Berni S, Macucci F, Scalacci E, Vezzosi P., Biol Trace Elem Res.2006 Feb; 109: 97-104).

It has recently been found that an elevation in extracellular magnesium leads to a significant increase in synaptic plasticity and synaptic density in cultured hippocampal neurons (Slutsky I, SadeghpourS, Li B, Liu G. neuron.2004Dec 2; 44: 835-49). Synaptic networks are thought to be involved in the organization of neural circuits in early development and in learning and memory. In fact, there is a large inverse correlation between the number of synapses and the extent of cognitive dysfunction in patients with Alzheimer's disease (Terry RD, Masliah E, Salmonon DP, Butters N, DeTeresara R, Hill R, Hansen LA, Katzman R.AnnNeurol.1991 Oct; 30: 572-80; Selkoe DJ.science.2002 Oct 25; 298: 789-91). Memory decline is also associated with synaptic loss during normal aging (Terry RD, Masliah E, Salmonon DP, Butters N, DeTeresara R, Hill R, HansenLA, Katzman R. Ann neurol.1991 Oct; 30: 572-80). Interestingly, the levels of magnesium in the brains of AD patients are lower than in normal subjects (Andrasi E, Pali N, Molnar Z, Kosel S. JAlzheimers Dis.2005 Aug; 7: 273-84; Cilliler AE, Ozturk S, Ozbakir S. Geronology.2007 Nov 8; 53: 419-22). Increasing magnesium in the brain may be beneficial in preventing synaptic loss and improving memory decline during aging and AD pathology.

Although magnesium has an important physiological role, it may not be consumed in a person's diet sufficiently. The average daily magnesium value for a national sampling of the United states is between 20 and 30 years of age, caucasian and 300mg, and black male 250 mg. In older adults older than 70 years, daily intake is also reduced to-200 mg due to reduced food consumption. On the other hand, men are advised to have a daily allowance (RDA) of 420 mg/day. Therefore, most american male populations may be deficient in magnesium, particularly during the aging process. Similar degrees of deletion were also present in the U.S. female population (Ford ES, Mokdad AH.J Nutr.2003 Sep; 133: 2879-82). Based on this study, most americans need to supplement their diets with an additional-200 mg/day magnesium. Interestingly, the magnesium contained in the food provides a relatively high magnesium absorption rate (-50%), which may mean that-100 mg/day of magnesium is still required to be absorbed into the human body. In general, most commercially available magnesium formulations have a magnesium uptake of ≦ -40%. For example, magnesium oxide is probably the most widely used magnesium supplement, with a magnesium uptake of only about 4% (Firoz M, Graber M. Bioavailability of UScom magnesium precursors. Magnes Res.2001 Dec; 14: 257-62)). The present invention provides a controlled release magnesium composition for use as a dietary supplement for magnesium.

Summary of The Invention

To supply a person with sufficient magnesium, very high doses of magnesium supplement are required to achieve the Recommended Daily Allowance (RDA). For example, 4 grams of magnesium oxide is required as an oral supplement. Sustained release magnesium compositions provide several advantages. Sustained release avoids excessive magnesium concentrations in the Gastrointestinal (GI) tract. Magnesium not absorbed in the gastrointestinal tract often leads to diarrhea. The slow release avoids the accumulation of unabsorbed magnesium and reduces such side effects. The invention discloses such dosage forms and uses thereof.

In one aspect, the present invention provides an oral dosage form comprising magnesium (Mg) and threonate (T), wherein the threonate comprises one or more threonate salts or threonate precursors, wherein the oral dosage form has an in vitro dissolution profile in dissolution media, and wherein the dissolution profile ranges from less than or equal to 5% in about 2 hours, less than 10% in about 4 hours, less than 40% in about 6 hours, greater than or equal to 60% in about 10 hours, and greater than or equal to 80% in about 12 hours, when measured using a usp type II (paddle) dissolution system at 75rpm and a temperature of 37 ℃.

In some embodiments, the magnesium and threonate in the oral dosage form are encapsulated in a tablet. In some embodiments, at least a portion of the magnesium (Mg) and threonate (T) are MgT₂Complexation in the form of a salt. In some embodiments, at least a portion of the magnesium (Mg) and threonate (T) are MgT₂The salt form is complexed and is present in an amount equal to at least about 20Mg by weight. In other embodiments, the molar ratio of threonate (T) to magnesium (T) is greater than or equal to about 0.1 to 2. In still other embodiments, the threonate precursor comprises threonic acid, a threonate ester, or a threonate lactone. In still other embodiments, the magnesium (Mg) is present in an amount greater than about 1 wt%. In further embodiments, the magnesium (Mg) is present in an amount greater than about 5 wt.%, or in an amount greater than about 7 wt.%.

In some embodiments, the magnesium (Mg) is complexed with an anion selected from chloride, taurinate, lactate, gluconate, citrate, malate, succinate, sulfate, propionate, hydroxide, oxide, orotate, phosphate, borate, salicylate, carbonate, bromide, stearate, amino acids, butyrate, aspartate, ascorbate, picolinate, pantothenate, nicotinate, benzoate, phytate, caseinate, palmitate, pyruvate, and threonate. In other embodiments, the oral dosage form further comprises a metal ion selected from the group consisting of calcium, potassium, sodium, chromium, iron, selenium, zinc, manganese, molybdenum, vanadium, and lithium. In other embodiments, the oral dosage form further comprises one or more antioxidants selected from the group consisting of resveratrol, ellagic acid, quercetin (quercetin), lipoic acid, and vitamin C.

In some embodiments, the dissolution profile ranges from less than 5% in about 2 hours, less than 10% in about 4 hours, less than 40% in about 6 hours, greater than or equal to 60% in about 10 hours, and greater than or equal to 80% in about 12 hours when measured using a usp type II (paddle) dissolution system at 75rpm and a temperature of 37 ℃. In some embodiments, the dissolution profile is zero order.

In some embodiments, at least 75% of the magnesium (Mg) and threonate (T) in the oral dosage form is provided in a controlled release dosage form. In some embodiments, at least 95% of the magnesium (Mg) and threonate (T) in the oral dosage form is provided in a controlled release dosage form. In some embodiments, 100% of the magnesium (Mg) and threonate (T) in the oral dosage form is provided in a controlled release dosage form.

In some embodiments, the dissolution medium is a saline solution. In some embodiments, the oral dosage form further comprises a polymeric binder mixed with magnesium (Mg) and threonate (T). In some embodiments, the polymer comprises polyvinylpyrrolidone. In some embodiments, the oral dosage form further comprises a pharmaceutically acceptable amount of magnesium stearate. In some embodiments, the oral dosage form further comprises one or more of polyvinylpyrrolidone, polyvinyl acetate, or propylene glycol.

In another aspect, the present invention provides an oral dosage form comprising from about 10Mg to 500Mg of elemental magnesium (Mg), wherein the oral dosage form is a controlled release formulation and the incidence of diarrhea is less than 20% upon administration of equal to or less than about 75 Mg/kg/day of the oral dosage form to Sprague-Dawley rats. In some embodiments, the incidence of diarrhea is less than 20% when administered at a dose equal to or less than about 75 mg/kg/day for at least about 3 days. In some embodiments, the dissolution rate of magnesium in the dosage form is about 40-80% dissolution in about 6 to 10 hours. In some embodiments, the incidence of diarrhea is less than 50% when the oral dosage form is administered at a dose equal to or less than about 130 mg/kg/day.

In another aspect, the invention provides an oral dosage form comprising magnesium (Mg) and threonate (T), wherein the threonate comprises one or more of a threonate salt or a threonate precursor, wherein the oral dosage form is effective to increase the lifespan of a subject on a high calorie diet. In some embodiments, administration of the oral dosage form to a subject on a high calorie diet results in protection such that the life span of the subject is comparable to the average life span of a subject of moderate weight. In some embodiments, the oral dosage form is administered to a human subject at a dose of about 1mg elemental magnesium/kg/day to about 16mg elemental magnesium/kg/day. In some embodiments, the oral dosage form increases survival by at least about 40% for subjects having a high calorie diet for at least about 60 weeks.

In another aspect, the present invention provides an oral dosage form comprising magnesium (Mg) and threonate (T), wherein said threonate comprises one or more of a threonate salt or a threonate precursor, wherein administration of said oral dosage form to a subject provides protection against adverse effects of a high calorie diet in said subject. Such adverse effects may include, but are not limited to, atherosclerosis, myocardial infarction, stroke, thromboembolism, metabolic syndrome, and diabetes. In some embodiments, the oral dosage form is administered to a human subject at a dose of about 1mg elemental magnesium/kg/day to about 16mg elemental magnesium/kg/day. In some embodiments, the oral dosage form increases survival by at least about 40% for subjects having a high calorie diet for at least about 60 weeks.

In another aspect, the present invention provides an oral dosage form comprising magnesium (Mg) and threonate (T), wherein said threonate comprises one or more of threonate or a threonate precursor, wherein said oral dosage form is readily absorbed or retained after administration of said oral dosage form to a subject, at least about 50% of said administered magnesium being absorbed by said subject, or at least about 30% of the magnesium administered to a subject being retained for a period of at least 2 days when said oral dosage form is administered at a dose of about 20 Mg/kg/day or greater.

In some embodiments, the subject is a Sprague-Dawley rat. In some embodiments, greater than about 60% of the administered magnesium is absorbed in the subject. In some embodiments, when the oral dosage form is administered at a dose of about 20 mg/kg/day or more, greater than about 40% of the administered magnesium remains for a period of at least 2 days. In some embodiments, the oral dosage form exhibits a dose-proportional increase in absorbed magnesium when administered to a subject in an amount of about 20 mg/kg/day to about 80 mg/kg/day.

In some embodiments, an oral dosage form of the invention comprises magnesium (Mg) and threonate (T), wherein said threonate comprises one or more of threonate or a threonate precursor, and wherein said oral dosage form, when administered to a subject, provides an increased concentration of magnesium in the cerebrospinal fluid of the subject, wherein the increased concentration of magnesium in the cerebrospinal fluid of said subject ranges from an increase of about 5% to an increase of about 10% after about 10 days of administration of said oral dosage form to said subject as compared to the baseline magnesium concentration without administration of magnesium.

In another aspect, the invention provides a method of treating a disorder associated with magnesium deficiency, comprising administering to a subject in need thereof an oral dosage form disclosed herein. In some embodiments, the condition is selected from the group consisting of neurological diseases, cardiovascular diseases, and metabolic disorders.

In yet another aspect, the present invention provides a method of increasing magnesium in the central nervous system of a subject in need thereof, comprising administering to the subject an oral dosage form provided by the present invention.

In yet another aspect, the present invention provides a method of maintaining a high calorie diet without significant risk of high calorie-related adverse effects, comprising administering to a subject in need thereof an oral dosage form provided by the present invention.

In yet another aspect, the present invention provides a method of supplementing magnesium to a subject in need thereof, comprising administering to the subject an oral dosage form provided by the present invention at least once daily.

In yet another aspect, the present invention provides a method of supplementing magnesium to a subject in need thereof, comprising administering to said subject an oral dosage form provided by the present invention at least twice daily for a period of 1 month or more.

The present invention also provides a method of making the above oral dosage form comprising mixing a powder comprising magnesium (Mg) and threonate (T), wherein both magnesium (Mg) and threonate (T) are present in salt form, with a polymer in an amount sufficient to produce particles comprising magnesium (Mg), threonate (T) and polymer, wherein the particles have a size sufficient to be retained on a 12 mesh screen. In some embodiments, the method further comprises filtering the particles using a 12 mesh screen to remove unbound threonate; drying the granules; adding a pharmaceutically acceptable amount of a lubricant to the particles; compressing the granules into one or more pellets having a size of between about 100mg to 2000 mg; and coating the one or more pellets with a polymeric coating film comprising one or more of polyvinylpyrrolidone, polyvinyl acetate, or propylene glycol.

Is incorporated by reference

All publications, patents and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference.

Brief Description of Drawings

The novel features believed characteristic of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the method of the invention is utilized, and the accompanying drawings of which:

figure 1 depicts a graph of the incidence of diarrhea in rats given different magnesium formulations. The y-axis is the incidence of diarrhea and the x-axis is the elemental magnesium dose per kg per day. The magnesium compound is magnesium citrate (MgCitrate), magnesium chloride (MgCl)₂) Magnesium gluconate (MgG), magnesium gluconate in milk (MgG + milk) and magnesium threonate (MgT).

Figure 2 depicts a series of graphs showing the absorption, reabsorption and retention rates of different magnesium formulations. The formulation comprises magnesium chloride (MgCl)₂) Magnesium citrate (MgCitrate), magnesium gluconate (MgG), magnesium glycinate (MgGly), and magnesium threonate (MgT). FIG. 2A depicts magnesium threonate (MgT) and MgCl for threose₂The relationship between magnesium (Mg) uptake and magnesium uptake. The absorbance was evaluated by linear regression. Figure 2B depicts the absorbance of different magnesium formulations expressed as a percentage. Figure 2C depicts the relationship between absorbed magnesium and magnesium excreted in urine. The excretion rate was estimated by linear regression. Fig. 2D depicts the excretion rates of different magnesium formulations expressed as a percentage. Figure 2E depicts the relationship between magnesium uptake and its retention in vivo. Retention was assessed by linear regression. Fig. 2F depicts the retention of different magnesium formulations expressed as a percentage.

FIG. 3 depicts the concentration of magnesium ([ Mg ] in cerebrospinal fluid after treatment with different formulations²⁺]_CSF) Is shown in the increase graph. y-axis shows [ Mg²⁺]_CSFAnd the x-axis represents time as days. The magnesium compound is magnesium chloride (MgCl)₂) Magnesium gluconate in milk (MgG + milk) and magnesium threonate (MgT).

FIG. 4A depicts survival curves of male mice supplemented and unsupplemented with magnesium threonate (MgT)

A wire. Fig. 4B depicts survival curves of female mice supplemented and unsupplemented with magnesium threonate (MgT).

Figure 5A depicts body weight of mice over time after feeding a standard or High Calorie (HC) diet.

Fig. 5B depicts mouse survival curves under a standard or high calorie diet. Mice on the high calorie diet had a shorter lifespan than mice on the standard diet. Mice on a high calorie diet plus MgT had a lifespan similar to mice on a standard diet.

Fig. 6A depicts a controlled release tablet comprising magnesium threonate. Fig. 6B depicts the release profile of a controlled release tablet comprising magnesium threonate formulated according to example 6.

Detailed Description

I. Controlled release oral dosage form

The present invention provides compositions comprising magnesium and threonate or a threonate precursor molecule formulated to delay or control release to provide a physiologically effective serum or plasma concentration sufficiently high over a desired period of time, but at a rate low enough to avoid adverse events associated with high levels of magnesium. Side effects associated with high Mg content include diarrhea. Controlled release of magnesium is desirable to reduce and delay peak plasma levels while maintaining bioavailability. Thus, physiologically effective levels are achieved while minimizing side effects associated with immediate release of the formulation. In addition, due to the time delay in obtaining peak serum or plasma levels, and the prolonged duration of therapeutically effective serum or plasma levels, the dose frequency is reduced, for example, to once or twice daily doses, thereby increasing subject compliance and compliance. For example, by using a controlled release formulation that extends the time to peak concentrations in the body, the severity and frequency of side effects associated with magnesium administration, including diarrhea, can be reduced, thereby reducing the change in magnesium concentration over time. Reducing the concentration change also reduces the concentration of the active ingredient at its maximum time point and provides a more stable amount of magnesium for a given time to treat a subject, which may further allow for increased dosages for the indication.

Controlled release within the scope of the present invention may refer to any sustained release dosage form. Non-limiting examples of sustained release dosage forms are described in U.S. patent application publication No. 2005/0129762 to Heaton et al and U.S. patent application publication No. 2007/0128279 to Edgren et al, which are incorporated herein by reference. Sustained release formulations are known in the art and are described in part in U.S. patent application publication No. 2006/0292221 to Sawada et al, which is incorporated herein by reference. For the purposes of the present invention, the following terms are considered to be essentially the same as controlled release: modified release, continuous release, controlled release, delayed release, depot, gradual release, extended release, programmed release, extended release, proportional release, delayed release, depot, lag, slow release, interval release, sustained release, time coat, timed release, delayed action, extended action, layered slow action, extended action, prolonged action, delayed action, repeated action, slow action, sustained action drugs, and extended release. Further discussion of these terms may be found in Lesczek Krowczynski, Extended-Release document Forms, 1987(CRC Press, Inc.). A wide variety of dosage forms are covered by various controlled release techniques. Controlled release techniques include, but are not limited to, physical systems and chemical systems.

The compositions, kits and/or methods described herein are useful for the purposes described herein, e.g., maintaining, enhancing and/or improving health, nutrition and/or other conditions and/or cognitive, learning and/or memory functions of a subject, such as, by way of example only, magnesium deficiency, Mild Cognitive Impairment (MCI), Alzheimer's Disease (AD), attention deficit disorder (ADHD), Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's disease, parkinson's disease, schizophrenia, diabetes, migraine, anxiety, mood and hypertension.

The compositions of the invention may be formulated in a slow release or sustained release form, i.e., to provide relatively consistent levels of magnesium threonate over an extended period of time. In some embodiments, the magnesium counterion composition and/or other therapeutic agent can be administered in combination or separately through the use of a controlled release dosage form. In one embodiment, the present invention provides an oral dosage form comprising magnesium (Mg) and threonate (T), wherein said threonate comprises one or more threonate salts or threonate precursors, wherein said oral dosage form has an in vitro dissolution profile in dissolution media, and wherein said dissolution profile ranges from less than or equal to 5% in about 2 hours, less than 10% in about 4 hours, less than 40% in about 6 hours, greater than or equal to 60% in about 10 hours, and greater than or equal to 80% in about 12 hours, when measured using a usp type II (paddle) dissolution system at 75rpm and a temperature of 37 ℃. In other embodiments, the dissolution profile ranges from less than 5% in about 2 hours, less than 10% in about 4 hours, less than 40% in about 6 hours, greater than or equal to 60% in about 10 hours, and greater than or equal to 80% in about 12 hours when measured using a usp type II (paddle) dissolution system at 75rpm and a temperature of 37 ℃. In other embodiments, the dissolution profile ranges from less than 5% in about 2 hours, less than 10% in about 4 hours, less than 40% in about 6 hours, greater than or equal to 60% in about 10 hours, and greater than or equal to 80% in about 12 hours when measured using a usp type II (paddle) dissolution system at 75rpm and a temperature of 37 ℃. In some embodiments of the oral dosage forms described herein, the magnesium and threonate are encapsulated in a tablet.

In some embodiments, at least 75% of the magnesium (Mg) and threonate (T) in the controlled release oral dosage forms of the present invention are provided in a controlled release dosage form. In some embodiments, at least 95% of the magnesium (Mg) and threonate (T) in the controlled release oral dosage form are provided in a controlled release dosage form. In some embodiments, 100% of the magnesium (Mg) and threonate (T) in the oral dosage form is provided in a controlled release dosage form. In some embodiments, the dissolution medium is a saline solution. In some embodiments, the dissolution profile is zero order, i.e., dissolution rate is independent of concentration.

The release profile, i.e. the extent of magnesium release over a desired time, can be conveniently determined for a given time by measuring the release under controlled conditions, for example using a usp dissolution apparatus. Preferred release profiles are those that slow the uptake of magnesium into the bloodstream while also providing therapeutically effective levels of magnesium. The dissolution of the active ingredient is measured at given intervals over a period of time according to standard dissolution test guidelines for controlled release ("CR") curves. A minimum of three time points are recommended, typically including the early, middle and late stages of the dissolution profile. The final measurement should not be earlier than the time point at which at least 80% of the active ingredient is dissolved (Guidance for Industry, "Extended Release object Forms: Development, Evaluation, and Application of In Vitro/In Vivo diagnostics, Food and Drug Administration, CDER, September 1997, page 17). Sufficient sampling is important: for example, samples are taken at 1, 2 and 4 hours and then every 2 hours until 80% of the active ingredient is released (guide for Industry, SUPAC-MR: Modified ReleaseSolid Oral Dosage Forms, "Food and Drug Administration, CDER, 9 months 1997, page 6). Preferred dissolution devices are devices I (basket) or II (paddle) of the United states Pharmacopeia, applied at approved rotation speeds, e.g., basket 100rpm, paddle 50-75rpm (guide for Industry, "Extended Release object Forms: Development, Evaluation, and Application of In Vitro/In Vivo diagnostics, CDER, 1997, 9 months, page 4). Controlled release dosage forms allow the release of the active ingredient over an extended period of time. On the other hand, a substance that dissolves in solution in the first 30 to 60 minutes is considered to have an immediate release ("IR") profile. (resolution Testing of electrolyte Release Solid Oral Dosage Forms, 8 months Release 1997, part IV-A). Thus, an immediate release solid oral dosage form allows for the release of most or all of the active ingredient within a short period of time, e.g., 60 minutes or less.

The subject compositions may comprise an active ingredient including magnesium, threonate, or a threonate precursor. In one embodiment, the subject composition comprises a magnesium counterion, as shown in the formula:

the composition may be suitable or advantageous in terms of prevention and/or treatment. Threonate is a natural metabolite of vitamin C or ascorbic acid, is non-toxic to animals (Thomas et al, FoodChem.17, 79-83(1985)) and is associated with biological effects in animals (e.g., promoting vitamin C uptake) (Verlaneri et al, Life Sci.48: 2275-2281 (1991)).

In some embodiments, the threonate salt comprises threonate and/or a threonate precursor molecule. Threonate may be in the form of a salt. The term "threonate precursor" generally refers to a precursor molecule that is readily converted to threonate when the composition is dissolved in an aqueous medium or ingested by ionization or hydrolysis with or without the aid of an enzyme. The precursor may be threonic acid, an ester derivative of threonic acid or threonate, or lactonized threonic acid. Generally, threonate as used in the present invention refers to L-threonate. For example, the L-threonate precursor may be L-threonic acid, an ester derivative of L-threonic acid or an ester of L-threonic acid, or lactonized L-threonic acid. In some embodiments, the invention uses D-threonate, or a precursor thereof.

In some embodiments, at least a portion of the magnesium (Mg) and threonate (T) are MgT₂Complexation in the form of a salt. In some embodiments, at least a portion of the magnesium (Mg) and threonate (T) are MgT₂A salt form complex present in an amount equal to at least about 20Mg by weight of Mg. In some embodiments, the molar ratio between the threonate (T) and the magnesium (Mg) is greater than or equal to about 0.1 to 2. In some embodiments, magnesium (Mg) is present in an amount greater than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% by weight. In some embodiments, magnesium (Mg) is present in an amount greater than about 1%, 5%, or greater than about 7% by weight.

The compositions of the invention generally comprise a sufficient amount (as further defined below) of magnesium ions (hereinafter "magnesium") and threonate or a threonate precursor molecule, wherein the magnesium or threonate may or may not be in the form of magnesium threonate in the composition. When magnesium is not in the form of magnesium threonate but is a further magnesium salt, the further magnesium salt may be any suitable inorganic or organic magnesium salt. Herein, the term "suitable" generally means that the anion of the magnesium salt is non-toxic. Examples of suitable salts include, but are not limited to, magnesium chloride, magnesium sulfate, magnesium oxide, magnesium acetate, magnesium lactate, magnesium citrate, magnesium malate, magnesium D-threonate, magnesium gluconate, magnesium taurate, and magnesium pyridonate. Likewise, when the threonate salt is not in the form of magnesium threonate, it may be in the form of another threonate salt containing another non-toxic cation. Suitable non-toxic cations include potassium, sodium, calcium and ammonium. In some embodiments, a suitable non-toxic cation is potassium. In general, the term "threonate" as used herein encompasses threonate and its precursors, including by way of example salts, acids, esters, and lactones.

In addition to magnesium threonate, the composition may comprise at least one magnesium-containing component (MCC) or magnesium-counter ion compound also useful herein. Examples of MCC include magnesium salts of amino acids, magnesium acetate, magnesium ascorbate, magnesium citrate, magnesium gluconate, magnesium lactate, magnesium malate, magnesium pyrrolidone carboxylate, and magnesium taurate. Other salts of the compositions disclosed herein include, but are not limited to: acid addition salts such as those made with hydrochloric, methanesulfonic, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, carbonic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexylsulfamic, salicylic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acids. The term "salt" may also include addition salts of the free acid or free base. All of these salts (or other similar salts) can be prepared in a conventional manner. All of these salts are acceptable provided that they are non-toxic and do not significantly interfere with the desired pharmacological activity.

The MCC composition of the present invention may comprise at least one non-acidified milk component sufficient to enhance the bioavailability of elemental magnesium associated with MCC. Examples of such ingredients include lactose, fatty acids or milk fat, and/or other organic ingredients thereof, for example, sufficient to achieve such enhancement. The ratio of the amount of elemental magnesium associated with the at least one MCC to the amount of said component by mass is from about 1 to about 5 to about 1 to about 3000. The composition is suitable for oral administration to a subject.

Magnesium threonate is a highly bioavailable form of a magnesium counterion composition. However, obtaining such magnesium threonate in vivo can be provided in a variety of ways. In some embodiments, the subject ingests magnesium threonate. In other embodiments, magnesium may be used with other supplements, resulting in the reconstitution of the magnesium counterion composition in vivo. Without being bound by theory, threonate may facilitate cellular uptake of any form of magnesium, and may also enhance delivery to the brain and central nervous system. Thus, in some embodiments, magnesium is provided that is not complexed with threonate, and threonate is provided to the same subject to enhance absorption. For example, magnesium gluconate and potassium threonate are administered at approximately the same time to cause reconstitution of magnesium threonate in the body and/or to enhance magnesium uptake and/or delivery of magnesium to the brain. In other examples, certain counterions may be metabolites of other substances. For example, vitamin C is metabolized in the human body into threonate ions; thus, the uptake of magnesium and vitamin C in a form that is absorbable by the body can result in the reconstitution of magnesium threonate in vivo. An example of another substance that is metabolized to threonate in the human body is ascorbate. Thus, in some embodiments of the invention, a subject may be provided magnesium ascorbate, which is metabolized in vivo to magnesium and threonate. Those skilled in the art will recognize that these examples are provided by way of example only, and that other combinations of magnesium compounds and secondary compounds may result in the reconstitution of magnesium counterion compositions in vivo.

Magnesium counter-ion compositions comprising more than one magnesium counter-ion compound may be suitable, advantageous or desirable relative to magnesium counter-ion compositions comprising a single magnesium counter-ion compound. Combinations of more than one magnesium counterion compound may be suitable, advantageous or desirable in any number of characteristics or factors (e.g., magnesium content, solubility, palatability, magnesium bioavailability, etc.). In terms of palatability, a combination of more than one magnesium counterion compound may be suitable, advantageous or desirable. Combinations of more than one magnesium counterion compound may be suitable, advantageous or desirable in terms of maintaining and/or enhancing one or more properties of the magnesium counterion compound or compounds.

The relative amount of the molar ratio of threonate to magnesium can be adjusted for various formulations. Generally, the mole ratio of threonate to magnesium is from about equal to 1/5. Since each MgT contains 2 threonate groups, this means that at least 10% of the Mg comes from MgT. Another 90% can be from MgCl₂Or other Mg salts. In some embodiments, the threonate salt to magnesium molar ratio is from ≧ 2/7. For example, this ratio corresponds to a nutritional formulation comprising, in a Recommended Daily Allowance (RDA) of 350Mg, about 50Mg of Mg in the form of MgT and about 300Mg of MgCl₂Or Mg in the form of other Mg salts. In other embodiments, the molar ratio of threonate to magnesium is about 2. In some embodiments, all of the threonate in the composition is in the form of magnesium threonate, which is an active ingredient of the composition. When the magnesium and threonate are each part of a separate compound in a composition and the composition is dissolved or orally ingested, then at least a portion of the magnesium and threonate will form magnesium threonate in situ as a result of the ion exchange reaction. In some embodiments, all of the magnesium and all of the threonate are from the same magnesium threonate compound, e.g., to minimize the mass of the composition. In some embodiments, when the molar ratio of threonate to magnesium is less than 2, a portion of the magnesium is derived from other magnesium compounds. In some embodiments, the additional magnesium compound is selected from the group consisting of magnesium chloride, magnesium taurate, magnesium lactate, magnesium gluconate, magnesium citrate, and magnesium malate.

The exact amount of magnesium used in a given dosage form of the invention will depend on the physical form of the composition. According to one embodiment, the present invention provides a solid or semi-solid composition comprising at least 1, 2, 3, 4, 5,6, 7, 8, 9, or 10% or more by weight elemental magnesium. According to one embodiment, the solid or semi-solid composition is a pellet comprising at least 20mg of elemental magnesium or at least 50mg of elemental magnesium or at least 80mg of elemental magnesium.

The controlled release composition of the present invention has many advantages. For example, the invention may also reduce the frequency of administration. For example, the controlled release compositions of the present invention can be used to administer magnesium less frequently than immediate release formulations (i.e., once a day (q.d.) versus twice a day (b.i.d.) or three times a day (t.i.d)), thereby improving subject compliance and caregiver convenience. In some embodiments, the compositions described herein are administered less frequently, e.g., every 2 days, every 3 days, weekly, or monthly. These compositions are particularly useful because they provide a biologically effective amount of magnesium from the beginning of administration, which further improves compliance and compliance, and enables an effective steady state magnesium concentration to be achieved in a shorter period of time. Furthermore, the compositions of the present invention, by virtue of their design, allow for safe administration at higher magnesium doses, again increasing the utility of these drugs in various indications.

The use of the controlled release dosage forms provided by the present invention allows magnesium to be released into a subject sample at a lower rate than that observed with an Immediate Release (IR) formulation having the same amount of magnesium. In some embodiments, the rate of change of the controlled release formulation over a specified time period from administration to a maximum concentration of the biological sample as measured by the change in concentration is less than about 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the rate of the IR formulation. Further, in some embodiments, the rate of change of concentration over time is less than about 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the rate of the IR formulation. In some embodiments, the rate of change of concentration over time is less than about 5% of the rate of the IR formulation.

In some embodiments, by increasing the time to reach the maximum concentration in a relatively proportional manner, the rate of change of concentration over time may be reduced. For example, increasing the time to reach maximum concentration by a factor of two may reduce the rate of change of concentration by a factor of approximately 2. Thus, magnesium may be provided to reach its maximum concentration at a significantly reduced rate than Immediate Release (IR) dosage forms. The compositions of the invention may be formulated to provide a maximum concentration change over 24 hours, 16 hours, 8 hours, 4 hours, 2 hours, or at least 1 hour. The rate of change in concentration is reduced by a factor of about 0.05, 0.10, 0.25, 0.5, or at least 0.8. In certain embodiments, this may be achieved by releasing less than about 30%, 50%, 75%, 90%, or 95% of the magnesium into the bloodstream within 1 hour of administration.

Optionally, the controlled release formulation exhibits a plasma concentration profile with an initial (e.g., from 2 hours after administration to 4 hours after administration) slope that is less than 75%, 50%, 40%, 30%, 20%, or 10% of the slope of an IR formulation of the same dose of the same magnesium. The exact slope for a given individual subject will vary depending on the magnesium threonate composition, the amount delivered, or other factors including, for example, whether the patient is eating. For other doses as mentioned above, the slope varies directly with dose.

By using the sustained release formulation or method of administration described herein, a therapeutically effective steady state plasma concentration of magnesium is achieved in the subject during the 3, 5,7, 9, 10, 12, 15, or 20 days from the start of administration. For example, when a formulation described herein is administered at a substantially constant daily dose (e.g., a dose ranging from 50Mg to 1000Mg, preferably from 100Mg to 800Mg, more preferably from 200Mg to 700Mg of elemental Mg per day), it reaches a steady state plasma concentration for about 70%, 60%, 50%, 40%, 30% or less of the time required to reach that plasma concentration using a dose escalation protocol.

In some embodiments, the release rate of magnesium of the present invention, as measured by a dissolution test at the first 1, 2,4, 6, 8, 10 or 12 hours, is less than about 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% of the rate of an IR formulation containing the same magnesium. In some embodiments, the release rate of magnesium of the present invention, as measured by a dissolution test at the first 2-4 hours, is less than about 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the rate of an IR formulation containing the same magnesium. In some embodiments, the release rate of magnesium of the present invention, as measured by the dissolution test at the first 2-4 hours, is less than about 5% of the rate of an IR formulation containing the same magnesium.

The controlled-release formulation provided by the present invention may take various forms. In some embodiments, the supplement composition of the present invention is administered in an oral dosage form, including liquid dosage forms (e.g., suspensions or slurries) and oral solid dosage forms (e.g., tablets or bulk powders). In some embodiments, the dosage form is provided as a tablet. The term "tablet" as used herein generally refers to tablets, caplets, capsules (including soft gelatin capsules) and lozenges. The average tablet size of round tablets is preferably from about 10Mg to 150Mg elemental Mg, while the average tablet size of capsule shaped tablets is from about 20Mg to 200Mg elemental Mg. Controlled release tablets are generally divided into three types: a scaffold, a reservoir, and a permeation system. While any of these three systems are suitable for use in the present invention, the latter two systems have more optimal properties of encapsulating a relatively large mass, which may be desirable for the present invention. In some embodiments, the sustained release tablet is based on a depot system in which a magnesium and threonate containing core is encapsulated by a porous membrane coating that upon hydration allows diffusion of the magnesium threonate. An effective daily dose for human use may be about 50 to 1000mg magnesium, which corresponds to 606 to 12119mg magnesium threonate. If the magnesium and threonate are from a source other than magnesium threonate, the mass range will change. Since the combined mass of the active ingredients is typically grams, a highly efficient delivery system can provide the best results.

An example of a controlled release tablet comprising magnesium threonate as the magnesium composition in the core, Polyvinylpyrrolidone (PVA) as the binder, magnesium stearate as the lubricant, and polyvinyl acetate (SR30D) as the matrix former in the coating, PVP as the pore former, talc and TiO as the inert powder and its release profile is shown in FIG. 6₂Propylene glycol as a plasticizer and lake dyes. See example 6 and table 1. Tablets of the above formulation exhibited a zero order release profile over 24 hours.

The present invention further provides methods of making the oral dosage forms described herein. Tablets are prepared by methods known in the art and may further comprise suitable binders, lubricants, diluents, disintegrants, coloring agents, flavoring agents, glidants, melting agents, all of which are known in the art. The oral dosage form of the present invention may optionally have a film coating to protect the components of the magnesium counterion supplement composition from one or more of moisture, oxygen, and light, or to mask any undesirable taste or appearance. Suitable coating agents include, for example, cellulose, hydroxypropyl methylcellulose. In some embodiments, the oral dosage form comprises a plurality of beads encapsulated in a capsule. This form is useful as a sustained release formulation. Other tablet forms may also be formulated in sustained release form. Methods for making sustained release tablets are known in the art, see, for example, U.S. patent publication nos. 2006/051416 and 2007/0065512, or other references disclosed herein.

In some embodiments, the oral dosage form of the invention is prepared by mixing a powder comprising magnesium (Mg) and threonate (T), wherein both magnesium (Mg) and threonate (T) may be present in salt form, with a polymer in an amount sufficient to produce particles comprising magnesium (Mg), threonate (T), and polymer, wherein the particles are of a size sufficient to be retained by a 12 mesh sieve. In some embodiments, the method further comprises: filtering the particles using a 12 mesh sieve to remove unbound threonate; drying the granules; adding an acceptable amount of a lubricant to the particles; the granules are compressed into one or more pellets having a size between about 100mg and 2000mg and the one or more pellets are coated with a polymeric coating film comprising one or more of polyvinylpyrrolidone, polyvinyl acetate, or propylene glycol. In some embodiments, pellets are prepared having an elemental magnesium content of about 10mg to about 200 mg. In some embodiments, the one or more forms of threonate contained in the dosage form comprise threonate of a threonate precursor molecule as described herein. For example, the precursor may comprise threonic acid, a threonate ester, or a threonate lactone.

In some embodiments, the compositions described herein are prepared using a formulation described in U.S. patent 4,606,909 entitled "pharmaceutical formulations. This document describes a controlled release multiple unit formulation which upon disintegration of the formulation (e.g. pellets or tablets) provides a plurality of units each coated or microencapsulated into the stomach of a subject (see e.g. column 3, line 26 to column 5, line 10, and column 6, line 29 to column 9, line 16). Each of these units, each coated or microencapsulated, contains a core of substantially uniform cross-section containing particles of a poorly soluble active substance, and the core is coated with a coating film that is substantially resistant to the conditions of the stomach but is erodible under the current conditions of the gastrointestinal tract.

In some embodiments, the compositions of the present invention are formulated using, for example, the method disclosed in U.S. patent 4,769,027 entitled "Deliverysystem". Thus, sustained release formulations of physiologically acceptable substances (e.g., sugars/starches, salts and waxes) can be coated with a magnesium-containing water-permeable polymeric matrix, which is then coated with a water-permeable membrane having dispersed therein a water-soluble particulate pore-forming material.

In some embodiments, for example, magnesium compositions are prepared as described in U.S. Pat. No. 4,897,268, entitled "Drug delivery system and method of making the same," which relates to biocompatible, biodegradable microcapsule delivery systems. Thus, magnesium can be formulated into a composition containing a blend of free-flowing spherical particles obtained by loading large amounts of magnesium individually into microcapsules of different copolymer excipients that biodegrade, for example, at different rates, to release magnesium into the circulation at a predetermined rate. Some of these particles contain a copolymer excipient so that the core active ingredient is released rapidly after administration and thus the active ingredient is delivered initially. The second fraction of particles contains the type of excipient such that when delivery of the first fraction begins to decline, the encapsulated ingredient begins to be delivered. The third fraction of ingredients may be encapsulated with a further different excipient such that the second fraction begins to be delivered when its delivery begins to decline. The delivery rate can be varied by, for example, changing the ratio of lactide/glycolide in the poly (D, L-lactide-co-glycolide) capsules. Other polymers that may be used include polyacetal polymers, polyorthoesters, polyamide esters, polycaprolactone and copolymers thereof, polycarbonates, polyhydroxybutyrate and copolymers thereof, polymaleimides, copolyoxalates, and polysaccharides.

In some embodiments, the compositions of the present invention are prepared as described in U.S. patent 5,395,626, which describes a multi-layered controlled release dosage form. The dosage form comprises a plurality of coated particles, wherein each coated particle has a plurality of layers around a magnesium-containing core, i.e., the magnesium-containing core and at least one other layer containing an active ingredient are covered by a controlled release barrier layer, thereby providing at least two controlled release layers having a water soluble composition in the plurality of coated particles.

In some embodiments, magnesium and threonate are described, for example, in U.S. Pat. No. 6,919,373 entitled "Methods and devices for providing managed devices", U.S. Pat. No. 6,923,800 entitled "synthetic delivery system, and method for controlling delivery rate of fibrous agents synthetic delivery systems", U.S. Pat. No. 6,929,803 entitled "Conversion of liquid filtered materials into controlled devices by synthetic systems", and U.S. Pat. No. 6,939,556 entitled "Minimy compatible, porous for fibrous materials deviceAre prepared by techniques, all of which are incorporated herein by reference. This technique provides precisely controlled delivery for up to 24 hours using osmosis and is applicable to many compounds, including those that are poorly soluble. OROSTechniques can be used to deliver high doses to meet high load requirements. By targeting to specific regions of the gastrointestinal tract, OROSThe technology can provide more efficient absorption and enhanced bioavailability of the active ingredient. OROSThe osmotic driving force and the protection of the active ingredient up to the time of release eliminate the absorption and metabolic differences occasionally caused by gastric pH and motility.

Formulations for Sustained long-term delivery are further provided, for example, in U.S. Pat. No. 6,797,283 entitled "therapeutic Retention and delivery multiple layers," U.S. Pat. No. 6,764,697 entitled "System for delivery drive up to seven hours," and U.S. Pat. No. 6,635,268 entitled "Sustainated delivery of an active agent using an implantable System," all of which are incorporated herein by reference.

In some embodiments, the controlled release dosage form of the present invention comprises a plurality of beads, wherein each bead comprises a core having a diameter of about 1 μm to about 1000 μm and the core comprises an active ingredient comprising magnesium or a salt thereof in a range of about 15 to about 350Mg/g dosage form, wherein the dosage form comprises less than about 2.5% of the adduct and the dissolution rate of the active ingredient is greater than about 80% within about 60 minutes of the start of entry of the dosage form into an environment of use. In some embodiments, the dissolution rate is greater than about 80% in 30 minutes.

In some embodiments, each bead comprises a core and a magnesium-containing active ingredient. Suitable bead forms of magnesium may comprise magnesium and threonate in admixture with soluble ingredients such as sugars (e.g. sucrose, mannitol, etc.), polymers (e.g. polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc.), surfactants (sodium lauryl sulfate, chremophor, tweens, spans, pluronic (etc.), insoluble glidant ingredients (microcrystalline cellulose, calcium phosphate, talc, fumed silica, etc.), coating materials (examples of suitable coating materials are polyethylene glycol, hydroxypropyl methyl cellulose, waxes, fatty acids, etc.), dispersions in suitable materials (examples are waxes, polymers, physiologically acceptable oils, soluble substances, etc.), or combinations thereof.

According to some embodiments, the core comprises sugar spheres (nonpareil seeds), microcrystalline cellulose or mannitol. In some embodiments, the core is a sugar sphere, USP (paulaurcrambury, n.j.). In some embodiments, the particle size of the core is from about 1 μm to about 1000 μm. In some embodiments, the particle size of the core is from about 300 μm to about 900 μm. In some embodiments, the particle size of the core is from about 450 μm to about 825 μm. In exemplary embodiments, the core may be coated to avoid interaction between the core and the active ingredient. For example, suitable coating materials include, but are not limited to, polyethylene glycol, hydroxypropyl methylcellulose, waxes, fatty acids, and the like.

In one embodiment, the spheres comprise a portion of a dosage form ranging from about 50Mg/g to about 500Mg/g, preferably from about 60Mg elemental magnesium/g oral dosage form (i.e., 60Mg Mg/g) to about 100Mg elemental magnesium/g oral dosage form (i.e., 100Mg Mg/g). The fraction of beads depends on the amount of other components (if any) used in the dosage form.

The core may be coated with magnesium, such as magnesium threonate. In one embodiment, the amount of magnesium threonate is from about 150Mg/g (or 12.4Mg Mg/g) to about 950Mg/g (or 78.4Mg Mg/g), preferably from about 500 to 900Mg/g (or 41.2 to 74.3Mg Mg/g), based on the weight of the entire IR bead. In other embodiments, the amount of magnesium is from about 15 to 300mg/g, preferably from about 25 to about 250 mg/g.

In one embodiment, magnesium threonate is added to the mixture of binder and glidant before coating the core. Glidants may be selected from, but not limited to, microcrystalline cellulose, calcium phosphate, talc and fumed silica. Glidants are used in amounts of 1.5mg/g to about 35 mg/g. In some embodiments, the glidant is about 1.5mg/g to about 30 mg/g. In some embodiments, the glidant is about 2.5mg/g to about 25 mg/g. In other embodiments, the glidant ranges from about 5mg/g to about 30 mg/g.

The binder may be selected from, but is not limited to, povidone (PVP), hydroxypropyl methylcellulose (HPMC, Opadry), hydroxypropyl cellulose (HPC), or combinations thereof. In one embodiment, where the binder is HPMC, the amount of binder ranges from about 15mg/g to about 30mg/g, preferably from about 15mg/g to about 25 mg/g. In other embodiments where the binder is povidone, the amount of binder ranges from 1.5mg/g to about 35mg/g, preferably from about 5mg/g to about 30 mg/g.

The mixture of active ingredient and binder/water/glidant may be prepared, for example, by mixing with a mixer for at least 15 minutes, at least 30 minutes, or at least 1 hour. The components may also be combined by methods that include blending, mixing, dissolution, and evaporation, or by using suspension.

The active ingredient/binder/inactive substance mixture may be deposited on the core, wet-mass and extruded, granulated or spray-dried. In one embodiment, the sugar spheres are preheated in the range of about 40 ℃ to about 55 ℃ prior to applying the mixture. The core is optionally coated with a seal coat film of about 2% w/w to about 10% w/w prior to application to the active layer. The encapsulating coating may be any suitable coating capable of separating any active ingredient from the core, for example a polymeric coating, such as EudragitHPMC, HPC, or a combination thereof. For this reason, the dissolution stability of the compositions of the invention (i.e. maintenance of the dissolution profile upon exposure to elevated temperatures) is also important.

In one embodiment, the sugar spheres are coated using a fluid bed Coater known in the art, such as Glatt Powder Coater and particle GPCG3(Ramsey, n.y.). The coating conditions, such as air flow rate, spray rate and atomization pressure, are generally controlled and known to those skilled in the art. The temperature of the product may range from about 43 ℃ to about 51 ℃. The air flow rate may range from about 5 to about 9 m/s. The spray rate may range from about 9 to about 42 gm/min. The atomization pressure may range from about 1.5 to about 2.0 bar. The beads are then dried in a fluidized bed in a coating apparatus at a temperature of about 45 ℃ to about 50 ℃ for at least 5 minutes. In some embodiments, the beads are dried for at least 15 minutes, or at least 30 minutes. Those skilled in the art will recognize that many alternative operating conditions and various types of instruments may also be used.

Once the IR beads form the magnesium threonate-containing core provided herein, the beads may optionally be additionally coated with a sealing coating film. The encapsulating coating film may be a polymer or combination of polymers that can be designed to be pH dependent or independent. In a preferred embodiment, the polymer used for the hermetic coating film is selected from, but not limited to, HPMC (Opadry)Colorcon，PA)、HPC、EudragitRL、EudragitE100、EudragitE 12.5、EudragitE PO、EudragitNE (e.g., NE 30D or NE 40D), and combinations of two or more of the foregoing. These polymers are insoluble in aqueous media, but exhibit pH independent swelling upon contact with aqueous fluids. In other embodiments, the IR beads are coated with a pH-dependent polymer that is soluble at a pH preferably greater than 5. In the IR bead formulation, the amount of seal coat film polymer ranges from about 0% w/w to about 40% w/w, preferably from about 0% w/w to about 10%w/w, more preferably from about 0% w/w to about 3% w/w.

Alternatively, the IR core may be coated with a coating film that rapidly disintegrates or dissolves for aesthetic, handling, or stability purposes. Suitable materials are polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polymethacrylates containing free amino groups, each of which may or may not have a plasticizer, and may or may not have an anti-tack agent or filler. It is generally believed that the addition of about 3% by weight of the core of coating material provides a continuous coating in this size range. The outer coating film may be selected from, but not limited to, HPMC (Opadry)Colorcon，PA)、HPC、EudragitRL、EudragitE100、EudragitE 12.5、EudragitE PO、EudragitNE and mixtures thereof.

Dissolution of the active agent (e.g., magnesium threonate) from the beads can occur by permeation into a bulk medium and diffusion through the polymer layer, which is controlled by the permeability and swelling properties of the polymer. In some embodiments, the modified release beads have a similar bioequivalent AUC (area under the curve, measure of bioavailability) as compared to an immediate release tablet dosage form and a reduction in maximum plasma concentration of at least 25% as compared to an immediate release tablet. The modified release beads show good tolerability and can be administered in a wide range of doses. In some embodiments, the maximum plasma concentration when administered in a single dose is less than about 85% of an immediate release tablet. In some embodiments, the AUC when administered in a single dose is within 75% to 130% of the immediate release tablet. This range is considered equivalent to whole body exposure.

All beads in a controlled release formulation are required not to be released immediately. This prevents dose dumping and reduces adverse events. In some embodiments, the average time to reach maximum plasma concentration ranges from about 5 to about 48 hours, or from about 5 to about 36 hours. In some embodiments, the beads have an in vitro release rate of greater than about 70% to about 80% in about 4 to about 12 hours. In some embodiments, the formulation has a release rate of about 30% to about 60% over about 2 to about 6 hours. In some embodiments, the formulation has a release rate of about 10% to about 50% or about 10% to 35% within the first hour of sustained release into the environment of use.

In other embodiments, the present invention provides a composite dosage form comprising an Immediate Release (IR) component and a Controlled Release (CR) component, wherein the immediate release component comprises a first plurality of beads, each bead comprising from about 15 to about 350mg/g of a first magnesium-or salt thereof-containing active ingredient of the dosage form, wherein about 80% of the first active ingredient dissolves at the beginning 60 minutes after the dosage form enters an environment of use; and wherein the modified-release component comprises a second plurality of beads, each bead comprising from about 15 to about 350mg/g of a second magnesium-containing or salt thereof active ingredient of the dosage form, wherein from about 70% to about 80% of the second active ingredient dissolves in from about 4 hours to about 24 hours after the dosage form enters an environment of use.

The composite dosage forms may be combined into a single dosage form having a single phase or multiphase profile. The amount of active ingredient (e.g., magnesium threonate) in the composition is measured in mg/dose, and ranges from about 2.5mg to about 100 mg/dose. Preferably, the dose contains 2.5mg to 80mg of active ingredient. In other embodiments, the dose is 3, 6,7, 9, 12, 14, 15, 20, 21, 28, 40, or 60 mg.

Compositions comprising IR and CR components may include magnesium in immediate release form in an amount of about 5% to about 90% of the composition of the invention. In some embodiments, the immediate release portion is about 10% to 60%. In some embodiments, the immediate release magnesium content is about 15% to 50%. The controlled release form of magnesium may make up the remainder of the active ingredient. Thus, the final composition provides an amount of immediate release magnesium followed by other amounts of slow/modified release after administration. The compositions of the invention may exhibit more than one peak in the plasma concentration/time profile at any dosing interval, depending on the particular active ingredient used, the relative amounts of the IR and CR components, and the dissolution properties of the CR component. Thus, a composition having a specific release profile can be obtained.

The composition comprising the IR and CR components may comprise any solid oral dosage form known in the art. For example, solid dosage forms for use in the present invention include beads. The beads are dose-proportional, i.e. the same proportion of different types of beads can be used for different doses without significantly changing the percentage of active ingredient released over time. For example, a 40mg dose will deliver twice as much magnesium as a 20mg dose, and bioavailability is also proportional. Different dosages can be obtained using different amounts of beads. Beads can be given various dissolution properties by mixing one or more types of beads having different dissolution properties or using a multi-layer coating as an additional layer of pharmaceutical ingredient on a polymer layer and subsequent coating film to make a single bead familiar to those skilled in the art. The beads can also have a wide range of drug loading. For example, the drug loading of magnesium beads on the beads is up to 500mg/g dosage form, depending on the form of magnesium, counter ion, etc. One skilled in the art will recognize that higher drug loading allows for smaller capsule sizes.

Extension of time to maximum plasma concentration correlates with the release rate of magnesium in the application environment, as compared to immediate release tablets. The rate of release of magnesium depends on many factors, including the composition and dissolution properties of the solid dosage form. By using different compositions containing a single bead or a combination of bead types, their respective release rates can be combined to achieve a desired plasma release profile. By selecting a release modifying polymer and combining the release modifying polymer and binder to impart different release characteristics to the resulting beads, beads having different release characteristics can be obtained. If desired, an outer coating film such as an enteric coating may also be used.

The beads or bead mixture may be used, for example, in suspension, filled into capsules, compressed into tablets, or filled into sachets. The one or more types of modified release beads may be mixed together or encapsulated, or sprinkled into the food of a subject. According to the present invention, the oral solid dosage form may be any of these forms. Preferably, the dosage form is a capsule.

In one embodiment of the invention, the beads are formulated into capsules using an encapsulation machine. Various capsule sizes are required to accommodate the strength and fill weight of the target formulation. The capsule size ranges from 00 to 5 for a fill weight of about 15mg to about 630 mg.

The particle size of the IR and CR beads in the dosage form depends on the technique used to prepare them. For powder technology (mixing, spray drying, dispersion, etc.), the particle size component is sub-micron to 500 μm; for the coating technique (Wurster)Top spray, bottom spray, spray drying, extrusion, layering, etc.) from 5 to 1700 μm; for the tabletting technique, 1-40 mm.

In addition to the active ingredients comprising magnesium and threonate, the oral dosage form of the present invention may comprise any amount of physiologically acceptable excipients, depending in part on the controlled release mechanism employed. "physiologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions upon administration to an animal or human, suitable examples being those that are pharmaceutically acceptable. "physiologically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Such media and substances for physiologically active substances are well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the magnesium threonate compositions is contemplated. Supplementary active ingredients may also be incorporated into the composition. "physiologically acceptable salts" include acid addition salts and are formed with inorganic acids such as hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxides, as well as such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. General techniques for formulation and administration are described in "Remington: the Science and Practice of pharmacy, 20 th edition, Lippincott Williams & Wilkins, Philadelphia, Pa. Examples of such preparations are tablets, capsules, pellets, powders, granules, dragees, gels, slurries, ointments, solutions, suppositories, injections, inhalants and sols.

By way of example, slow or modified release oral formulations may be prepared using other methods known in the art. For example, a suitable sustained release form of the magnesium threonate composition provided herein can be a matrix tablet or capsule composition. Suitable matrix-forming materials include, for example, waxes (e.g., carnauba wax, beeswax, paraffin wax, ozokerite wax, shellac wax, fatty acids, and fatty alcohols), oils, hardened oils or fats (e.g., hardened rapeseed oil, castor oil, tallow, palm oil, and soybean oil), and polymers (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and polyethylene glycol). Other suitable matrix tablet materials are microcrystalline cellulose, powdered cellulose, hydroxypropyl cellulose, ethyl cellulose, and other carriers and fillers. Tablets may also contain granules, coated powders or pellets. The tablet may also be multilayered. Multilayer tablets are advantageous when the active ingredients (e.g. different forms of magnesium and threonate) have significantly different pharmacokinetic profiles. Optionally, the finished tablet may be coated or uncoated.

The coating composition typically comprises an insoluble matrix polymer (e.g., about 15-85% by weight of the coating composition) and a water-soluble material (e.g., about 15-85% by weight of the coating composition). Optionally, enteric polymers (about 1-99% by weight of the coating composition) may be used or included. Suitable water-soluble materials include polymers such as polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and monomeric materials such as sugars (e.g., lactose, sucrose, fructose, mannitol, and the like), salts (e.g., sodium chloride, potassium chloride, and the like), organic acids (e.g., fumaric acid, succinic acid, lactic acid, and tartaric acid), and mixtures thereof. Suitable enteric polymers include hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, shellac, zein, and carboxyl group-containing polymethacrylates.

The coating composition may be plasticized depending on the nature of the coating mixture, such as the glass transition temperature of the principal component or mixture of components or the solvent used to apply the coating composition. Suitable plasticizers may be added at 0 to 50% by weight of the coating composition and include, for example, diethyl phthalate, citric acid esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrates, dibutyl sebacate and castor oil. If desired, the coating composition may include fillers. Fillers can be used in amounts ranging from 1% to about 99% by weight of the total coating composition and can be insoluble materials such as silica, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, MCC, or polacrilin potassium.

The coating composition can be applied as a solution or latex in an organic or aqueous solvent or a mixture thereof. If a solution is used, the amount of solvent is about 25 to 99% based on the total weight of dissolved solids. Suitable solvents are water, lower alcohols, lower chlorinated hydrocarbons, ketones or mixtures thereof. If a latex is used, the amount of solvent is about 25-97% based on the amount of polymeric material in the latex. The solvent may be primarily water.

The compositions of the present invention include one or any combination of excipients such as, but not limited to, diluents, binders, disintegrants, glidants, lubricants, colorants, flavoring agents, solvents, film forming polymers, plasticizers, opacifiers, anti-adherents and polishing agents. The compositions of the present invention may be formulated using any one of the following excipients or a combination thereof.

Table 1: excipient

The magnesium compositions described herein may also include carriers such as solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and substances for pharmaceutically active substances is well known in the art. Acceptable salts may also be used in the composition, for example mineral salts such as hydrochlorides, hydrobromides, phosphates or sulphates, and salts of organic acids such as acetates, propionates, malonates or benzoates. The composition may also contain liquids such as water, saline, glycerol and ethanol, and substances such as wetting agents, emulsifying agents or pH buffering agents. Liposomes such as those described in U.S. Pat. No. 5,422,120 entitled "therapeutic Liposomes", PCT application WO 95/13796 entitled "therapeutic with Controlled Release of Actives", or WO 91/14445 entitled "therapeutic Liposomes", or European patent EP 524,968B 1may also be used as carriers.

The oral dosage forms of the present invention may contain various excipients. Surfactants useful as compressibility enhancers in the present invention generally include various physiologically acceptable, e.g., pharmaceutically acceptable surfactants. Suitable anionic surfactants include, for example, those containing carboxylate, sulfonate, and sulfate ions. Those containing carboxylate ions, sometimes referred to as soaps, are typically prepared by saponification of natural fatty acid glycerides in alkaline solution. The most common cations associated with these surfactants are sodium, potassium, ammonium and triethanolamine. The chain length of the fatty acids ranges from 12 to 18. Although there are many alkyl sulfates that can be used as surfactants, one particularly preferred surfactant is sodium lauryl sulfate (sodium lauryl sulfate) having an HLB value of about 40.

In the field of formulations, sodium lauryl sulfate is used as an emulsifier in an amount up to about 0.1% by weight of the formulation. Lauryl sulfate sodium salt is a water-soluble salt that is prepared as a white or cream powder, crystals or tablets, and is used as a wetting agent and disintegrant. The sodium lauryl sulfate salt, also known as sodium lauryl sulfate, is in fact a mixture of sodium alkyl sulfates that consists essentially of the sodium lauryl sulfate salt. The sodium lauryl sulfate salt is also known as sodium lauryl sulfate salt. Furthermore, lauryl sulfate sodium salt is readily available in solid form and solution from commercial sources (e.g., Sigma or Aldrich). The solubility of the sodium lauryl sulfate salt was about 1mg per 10ml of water. The fatty acids of coconut oil consist primarily of lauric acid, which upon catalytic hydrogenation form the corresponding alcohols. The alcohol is then esterified with sulfuric acid (sulfation) and the resulting alkyl hydrogen sulfate (alkyl sulfuric acid) is converted to the sodium salt by reaction with a base under controlled pH conditions.

Alternative anionic surfactants include docusate salts, such as the sodium salt thereof. Other suitable anionic surfactants include, but are not limited to, alkyl carboxylates, acyl lactylates, alkyl ether carboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acyl glutamates, fatty acids, polypeptide condensates and sulfates.

In other aspects of the invention, amphoteric (amphiphilic/amphipathic surfactants), nonionic surfactants and/or cationic surfactants are included in the co-process compositions of the invention. Suitable nonionic surfactants are, for example, polyoxyethylene compounds, lecithin, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, ethoxylated/propoxylated block polymers, propoxylated esters, alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols, ethylene glycol esters, diethylene glycol esters, propylene glycol esters, glycerol esters, polyglycerol fatty acid esters, spans (e.g. sorbitol esters), tweens (i.e. sucrose esters), glucose (dextrose) esters and polydimethylsiloxanes.

Other suitable surfactants include acacia, benzalkonium chloride, cholesterol, emulsifying waxes, glyceryl monostearate, lanolin alcohol, lecithin, poloxamers, polyoxyethylene and castor oil derivatives. Those skilled in the art will further recognize that the name of the surfactant used in the present invention and/or the method of preparation is not critical to the usefulness of the product.

Highly polar molecules may also be used as compressibility enhancers. Such highly polar molecules include certain dyes, particularly those that can bind to the cellulose surface and then create a relatively hydrophobic environment due to the presence of hydrophobic portions (e.g., hydrophobic tails) of the molecule, which "stand off" from the cellulose surface and block hydrophilic surface-to-surface cellulose interactions, such as hydrogen bonding. Preferably, the dye is physiologically (e.g. pharmaceutically) acceptable for incorporation into a solid dosage form.

Examples of suitable dyes include congo red (chemical name: 3, 3 ' - [ [1, 1 ' biphenyl ] -4, 4 ' -diylbis- (azo) ] bis [ 4-amino-1-naphthalenesulfonic acid ] disodium salt); FD & C Red No. 40 (also known as "allura Red") (chemical name: 6-hydroxy-5 [ (2-methyl-4-sulfophenyl) azo ] -2-naphthalenesulfonic acid disodium salt); FD & C yellow No. 5 (common name: tartrazine) (chemical name: 5-oxo- (p-sulfophenyl) -4- [ (p-sulfophenyl) azo ] -2-pyrazoline-3-carboxylic acid trisodium salt); FD & C yellow No. 6 (common name: sunset yellow FCF) (chemical name: disodium salt of 1-p-sulfophenylazo-2-naphthol-6-sulfonic acid); carmine (Ponceau 4R) (chemical name: 2-hydroxy-1- (4-sulfonato-1-naphthylazo) naphthalene-6, 8-disulfonate trisodium); brown HT (chemical name: disodium 4, 4' - (2, 4-dihydroxy-5-hydroxymethyl-3, 3-phenylenediazo) bis (naphthalene-1-sulfonate)); sparkling black BN (chemical name: 4-acetamido-5-hydroxy-6 [ 7-sulfonato-4- (4-sulfonato phenylazo) -1-naphthylazo ] naphthalene-1, 7-disulfonic acid tetrasodium salt); red acid dye (Carmoisine) (chemical name: disodium 4-hydroxy-3- (4-sulfonato-1-naphthylazo) naphthalene-1-sulfonate); blue acid red (chemical name: 2-hydroxy-1- (4-sulfonato-1-naphthylazo) naphthalene-3, 6-disulfonic acid trisodium); and mixtures thereof.

Other highly polar molecules that may be used as compressibility-enhancing agents include the optional other active agents themselves. For example, it is well known to those skilled in the art that certain classes of drugs (e.g., antipsychotic drugs) are highly polar in nature and may be used as compressibility-enhancing agents in accordance with the present invention.

The useful concentration range of the selected surfactant depends in part on its molecular weight and also on its degree of foaming, particularly when an agitated slurry to be sprayed to form the desired particles is present. Thus, for the aspect of the invention where a surfactant other than sodium lauryl sulfate is co-treated with magnesium threonate, it is understood that the surfactant is present in an amount that enhances the compressibility of magnesium threonate, but does not have a degree of foaming that significantly inhibits spray drying.

In one embodiment using a spray drying step, an aqueous dispersion of magnesium threonate, a compressibility enhancing agent (e.g., a surfactant or silica), and sufficient hot air are mixed together to produce evaporation and drying of the droplets. The highly dispersed slurry may be pumped or atomized. It is sprayed into the hot filtered air stream, supplying heat for evaporation, and transporting the dried product to a collection device. The air is then depleted by the removed water. The resulting spray-dried powder particles are nearly spherical in shape and uniform in relative size, and thus have good flowability. The co-processed particles need not be uniform or homogeneous. Other drying techniques may also be used, such as flash drying, ring drying, micron drying, tray drying, vacuum drying, radio frequency drying and possibly microwave drying.

Alternatively, all or a portion of the excipients may be wet granulated with the active ingredient. Representative wet granulation involves loading the new excipient granules into a suitable granulator such as those provided by Baker-Perkins and granulating with the active ingredient, preferably using an aqueous granulation liquid. In some embodiments, a portion of the total amount of the novel excipient is granulated with the active ingredient, and then an additional portion of the novel excipient is added to the granulation. In yet other embodiments, the additional portion of the novel excipient added to the excipient/active ingredient particles may be replaced with other excipients commonly used by those skilled in the art, depending of course on the needs of a particular formulation.

In other embodiments of the invention, further materials are added to the magnesium threonate and/or the compressibility-enhancing agent. Such additional materials include silica, non-silicon metal oxides, starch derivatives, surfactants, polyalkylene oxides, cellulose A ethers, cellulose esters, mixtures thereof, and the like. Further specific materials that may be included in the aqueous slurry (and thus in the resulting aggregated microcrystalline cellulose excipient) are alumina, stearic acid, kaolin, polydimethylsiloxane, silica gel, titanium dioxide, diatomaceous earth, corn starch, high amylose corn starch, high amylopectin corn starch, sodium starch, glycolic acid, hydroxylated starch, modified potato starch, mixtures thereof, and the like. It will be apparent to those skilled in the art that these excipients may be incorporated in the required amounts.

In addition to one or more active ingredients, other excipients known to those skilled in the art may be added to the novel excipients prior to preparation of the final product. For example, any of the commonly accepted soluble or insoluble inert filler (diluent) materials may be added to the final product (e.g., solid dosage form) if desired. Such inert fillers may include monosaccharides, disaccharides, polyols, inorganic phosphates, sulfates or carbonates, and/or mixtures thereof. Examples of suitable inert fillers include sucrose, glucose, lactose, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, calcium carbonate, microcrystalline cellulose, mixtures thereof, and the like.

An effective amount of any commonly accepted lubricant (including calcium or magnesium soaps) may optionally be added at the time of magnesium addition or in any case prior to compression into a solid dosage form. The lubricant may comprise, for example, magnesium stearate in any amount of about 0.5-3% by weight of the solid dosage form. In embodiments where the surfactant is part or all of the compressibility enhancing agent, no additional lubricant is required.

The total mixture is in an amount sufficient to produce a batch of uniform tablets that are then tableted in a conventional production scale tableting machine at the normal compression pressure of the machine (e.g., about 1500-. The mixture should not be compressed to such an extent that it is difficult to hydrate when exposed to gastric fluid.

The tablets of the present invention may also contain effective amounts of colorants (e.g., titanium dioxide, F.D. & C. and D. & C. dyes; see Kirk-Othmer Encyclopedia of Chemical Technology, Vol.5, p. 857- & 884, which is incorporated herein by reference), stabilizers, binders, odor control agents, and preservatives.

In some embodiments, magnesium (Mg) is complexed with an anion selected from chloride, taurinate, lactate, gluconate, citrate, malate, succinate, sulfate, propionate, hydroxide, oxide, orotate, phosphate, borate, salicylate, carbonate, bromide, stearate, an amino acid, butyrate, aspartate, ascorbate, picolinate, pantothenate, nicotinate, benzoate, phytate, caseinate, palmitate, pyruvate, and threonate. In some embodiments, the oral dosage form comprises a metal ion selected from the group consisting of calcium, potassium, sodium, chromium, iron, selenium, zinc, manganese, molybdenum, vanadium, and lithium. In some embodiments, one or more antioxidants, such as resveratrol, ellagic acid, quercetin, lipoic acid, or vitamin C, are added to the composition.

In addition to the excipients listed above, the oral dosage form of the present invention may also contain one or more chemicals or one or more extracts obtained from nature. Listed below are examples of nutritional and health ingredients provided according to the present invention.

Examples of nutritional ingredients that can be combined with magnesium threonate include: 5-HTP (5-hydroxytryptamine), 7-keto-DHEA (dehydroepiandrosterone), acetate, acetyl-L-carnitine, AE-941, alpha-carotene, alpha-hydroxy acid, alpha-phenylalanine, alpha-ketoglutarate, alpha-galactosidase, alpha-linolenic acid, alpha-lipoic acid, alpha-tocopherol, SHA-10, androstenediol, androstenedione, arginine, aspartic acid (aspartate), ascorbic acid, beta-alanine, beta-alanyl-L-histidine, beta-carotene, beta-cryptoxanthin, beta-D-fructofuranosidase, povidone iodine (betadine), beta-glucan, beta-polysaccharide, betaine, beta-sitosterol, acetyl-L-carnitine, AE-941, alpha-hydroxy acid, alpha-phenylalanine, alpha-ketoglutarate, alpha-galactosidase, alpha-linolenic acid, alpha-lipoic acid, alpha-tocopherol, SHA-10, androstenediol, androstenedione, arginine, Beta-tocopherol, BMS-214778, calcium carbonate matrix, calcium phosphate, caprylic acid, canthaxanthin, CDP-choline, chelated calcium, cholecalciferol, choline, chondroitin sulfate, citicoline, citric acid, creatine, cryptoxanthin, cysteine, D-calcium pantothenate, dehydroepiandrosterone, -tocopherol, panthenol, iron dextran, DGL (deglycyrrhizinated citrate), EA (dehydroepiandrosterone), cobalamin (dibencizzide), dichloroacetate, dimethylglycine, dimethylsulfone, disodium astaxanthin succinate, D, L-phenylalanine, DMAE (dimethylaminoethanol), D-mannose, DMSO (dimethyl sulfoxide), docosahexaenoic acid, docusate sodium (docusate sodium), eburnamenine (eburnamenine) -14-carboxylic acid, EDTA (EFEDTA), EDTA (ethylene diamine tetra-acetic acid), A (essential fatty acid), and/or D-fatty acid, Ellagic acid, eicosapentaenoic acid, ferric gluconate, ferrous sulfate, 5-hydroxytryptophan, flavonoids, folic acid analogs, folates, folic acid, forskolin, fructo-oligosaccharides, GABA (gamma-aminobutyric acid), galantamine hydrobromide, gamma-carotene, gamma-linolenic acid, gamma-oryzanol, gamma-glutamylcysteinylglycine, gamma-tocopherol, glucosamine sulfate, glutamine, glutamic acid, glutathione, glycerol, glycerophosphocholine, glycine, histidine, HMB (beta-hydroxy-beta-butyric acid methyl ester monohydrate), hydroxycobalamin, hydroxycitric acid, hydroxymethylbutyrate, hydroxytryptophan, butylbromide (scopolamine), hydroxylysine, hydroxyproline, inosine, hydroxol, glycofurosine, glycofuroxan (scopolamine), hydroxycobalamin, etc, Indole-3-methanol, inosine, inositol nicotinate, inositol hexaphosphate, erythorbic acid, isoflavone, isoleucine, lactic acid, L-arginine, L-ascorbic acid, L-asparagine, L-carnitine, L-dopa, leucine, L-phenylalanine, L-tryptophan, N-acetyl-2-benzyltryptamine (luzindole), lycopene, lysine, malic acid, mesoglycan, methionine, mecobalamin, methylguanylacetic acid, dimethylsulfone, monounsaturated fatty acids, N-3 fatty acids, N-acetylcysteine, N-acetyl D-glucosamine, N-acetyl-5-methoxytryptamine, N-acetyl aspartic acid, NADH, nicotinic acid, nicotinamide adenine dinucleotide, nordihydroguaiaretic acid (NDGA), Octacosanol, octanoic acid, oleuropein, omega-3 fatty acid, omega-6 fatty acid, omega-9 fatty acid, PABA (p-aminobenzoic acid), pangamic acid, pantethine, pantothenic acid, perillyl alcohol, PGG-glucan, phenyl acetate, lecithin, phosphatidylserine, phytoestrogen, phytomenadione, phytosterol, polyphenol, polysaccharide-K, polyunsaturated fatty acid, povidone iodine, potassium aspartate, potassium phosphate, polyvinyl pyridone iodine, pregnenolone, progesterone, provitamin A, pteroylglutamic acid, pyridoxine, pyridoxal-5-phosphate, quercetin-3-rhamnoside, quercetin-3-rutinoside, quinine, resveratrol, retinol, riboflavin-5-phosphate, Salicin, salicylate, SAM-E (S-adenosylmethionine), sitostane, sitosterol glucoside, sodium alginate, sodium ascorbate, sodium chloride, sodium ferric gluconate, sodium iodide, sodium phenylacetate, sodium phosphate, sorbic acid, stigmasterol, sulforaphane, phenylephrine, tannic acid, theanine, theobromine, thiamine, lipoic acid, tocopherol, tocotrienol, triacylglycerol esterase, choline citrate (TRI), troxerutin, tryptophan, tyrosine, acetyl-L-tyrosine, ubidecarenone, ubiquinone, ursolic acid, usnic acid, valine, vitamin a, vitamin B1, vitamin B12, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B9, vitamin Bx, vitamin C, vitamin D2, vitamin D3, vitamin E, Vitamin G, vitamin H, vitamin K, vitamin M, vitamin O, vitamin Q10, xylitol or zeaxanthin.

Examples of nutritional ingredients that may be incorporated into the herbs or natural extracts of magnesium threonate include: herba Verbasci Thapsi, herba Abelmoschi Manihot, semen abri Precatorii, folium Artemisiae Argyi, Tabanus, and acaciaAcacia, acai, acerola, cichorium, chicory (achicoriria), yarrow, annatto, chia, aconite, aconitum naviculum, acorus, cimicifuga, kiwifruit, adam needle fiber, oleander (adelfa), cyperus, poncirus indica, horse chestnut, african wild potato, brazil, agave, sisal, agrimony, agrimonia odorata, agrimoniaprocera, agrimony, creeping agrimony, avocado virus, alanine, albahaca morada, albaricoque, albarinoza, agrimonoza, matsutake, alcula, aldicara, aloe, arguaca, algaroo, algin, phytochrome, aca, onion, garlic, leek, allspice, aldela skin, aloe vera, gawa, garcinia, aloe vera, gawa, garcinia, aloe vera, garcinia camomile, aloe vera, kola, garcinia camomile, aloe vera, ko, Senna, veratrum, quince, peppermint, scutellaria, valerian, water lily, taxus, para-aminobenzoic acid, gooseberry, avocado, amomum, cashew, pineapple, anapsos, taurus, reseda, melia (andrioba), andrographis, anemonne acutiloba, angelica, angel's bark, angostura trifoliata, an estillado, rosewood, carica papaya, mugwort, neem, chamomile platycodon, sasanqua, anthonoma, anticancer ketones (anticalestones), awamori a (synechocystis), chinese bee, apis, celery, hemp, apple vinegar, apricot, peanut, arbuscular fricasse, arbutin, bursin, crataegus, taraxacum, burdocarpium, areca catechu, burclover, burcloves, areca catechu, burcloves, burclover, burclove, Artichoke, Artocarpus heterophyllus, Arthron japonicus, Ferula asafoetida, Asarum sieboldii, Asarum alternifolia, Chlamydomonas, Panax ginseng, Papaw fruit, Papaw tree, seaweed, Asabar filiformis, Asparagus officinalis, Arctium indicum, Populus alba, Graptopetalum album, astaxanthin, astaxanthina, Lobelia americana, tragacanth (astra galo), Astaraxacum, Astragalus membranaceus, Atractylis atropaEggplant, Australian tea tree oil, colchicum, aveloz, oat extract, avocado, Azadirachta indica, Morinda officinalis, Brazilian palm, Echinacea angustifolia, Echinacea tridaea, Echinacea trifolia, Bacopa monnieri, Scutellaria scleroderma, Scutellaria baicalensis, ballota nigra, Olibanum, balsamic grass, bamboo, Banchou tulip, Banxia Magnolia decoction, indigo of North America, Broccoli West strawberry, Funiu flower, burdock, Sucus ambrosia, bay leaves, laurel fruit, shallot, bearberry, caraway, melia, bee pollen, beets, bejuncode cerca, bellcho (ephedra herb), Piper, Bellis, marguerite, bentonite, berberiberiberina, Berberina, Berberidactylum, bergamot oil, beta-mugwort leaf, Areca catechu, Cassia, Liquidambar, Bifidobacterium, Betula, Bittersweet orange, Bittersweet, Balsam pear (bitter gourd), lime, bitter gourd, amaranth, annatto, biznaga, senna, black cohosh, black currant, black locust, black mulberry, black mustard oil, black pepper, black seed, black tea, blackberry, black cherry, black walnut, fucus, silybum marianum, ajuga, sanguinaria canadensis, peonies cyanea, Douglas indicus, blue ticket (aconite), blueberry, blue green algae, blusherum, leafflower, bluegrass, borage, borforsin, Boswer's milk, mastic, boswellia, bovine cartilage, yellow poplar, salmony, Chinese cabbage, black mustard, cabbage, Brazilian vetch, bromelain, sorghum, mandragora, datura, b-sitosterol, Bulby, plantain, bush bark, taraxacum, Bucky leaf, Bucky leaf, Coltsfoot, boxwood, rose mallow, prickly pear, caja oil, calaguala, calamus calcitriol, calendula, datura, Escholtzia californica, calabash, bovine colostrum, tea, campesterol, camphor, Canadian hemp, cancer weed, hemp, rapeseed oil, Mylabris, shepherd's purse, capsicum, balsam pear, caraway oil, carbohydrate supplement, cardamom, cardo bendonotito, cardo lechero, papaya, carnitine, carnosine, carob, carotene, carqueja (hops), carrageenGum, carrot, safflower, cascara sagrada, cashew, horse chestnut, castor oil, castor bean, Cordyceps sinensis, Arabic tea, catnip, centella asiatica, Carbamba, Cimicifuga racemosa, capsicum, barley, cebola albarana, Cebola alberrana leaf oil, Chelidonium majus, henna, Centaurea benedicta, Centaurea, centella asiatica, Agave (Agave americana), iperus communis, Petasites carota, Cervus nippon, Cera flava, citronella, Chrysanthemum indicum, Chamomile, Elysees microphylla, Eriocheir sinensis, Cera lilac, Chelidonium majus, Chenopodium album, Echinacea, Gordonia euryalis, Stellaria, chickweed, Capsicum, Chinese rose, Angelica sinensis, Lycium barbarum, Chinese hairy rehmannia glutinosa, Hedychium officinarum, Illicum, Italian, Poncirus trifolium, Poncium album, Poncirus trifolium album, Poncirus, Po, Cichorium, Coccidium, cider vinegar, cimicifuga racemosa, Cinnamomum cassia, Citriotus stannum, citrillus colocynthis, Cymbopogon citratus, citrulline, Citrus aurantium, Citrus reticulata, grapefruit, orange, Claviceps, clavo de olor, Clavo mushroom, Eugenia caryophyllata, Lycopodium, cnidium monnieri, cobalt, coca, papyrus, Citrus horrida, Cochloa, Crataegus, Cochlearia armoracqa, Cochloa, Cochlearia armoralis, Cochloa, Cohosh regro, Colorchis, Narcissus, Colubrina arborescens, Boraginaceae, Commifolia mukumula mukul, Myrrha, Commiphora, Combreda, Cordanthus, Calycota, Paecio paprika, Cordyceps sinensis, Coriolus, Cornus officinalis, Cornus, Cor, Folium Artemisiae Argyi, cottonseed oil, Populus deltoides, Imperata cylindrica, radix Saposhnikoviae, herba Apii graveolentis, Pangolin plants of Leguminosae, western primula sikkmensis (herba Tagetis Craifolii), Eriocheir sinensis, caulis Viburni Dilatae, Vaccinium myrtillus, Populus longus, fructus crataegi, dill, brush tree shrub, Cucurbita pepo, Juniperus communis, Curcuma rhizome, curcumin, rumex crispa, cusaria febrifuga, custara trifoliata, resveratrol, Annona squamosa, guar, cyanocobalamin, Cymbopogon, artichoke, and Cyperus rotundusCypress, cypress acauli, cypripedium, betain, caragana, rhubarb licorice soup, daisy, damiana, dandelion, codonopsis pilosula (or salvia), date palm, stramonium, datura sauveolens, stramonium, datura wrightii, carrot, belladonna, danol, velvet, caraway, claw hook grass, magic stick, rehmannia, dientede le, diet, longevity, dietary fiber, dietary sugar, digitalis, cardamom, dioconoacymus, dioconoa villosa L, divaricate's sage, dogwood, dohos pruriens, dolomite, angelica, D pantothenic acid, D-phenylalanine, emu, celosia plant, celosia, cudweed, hemlock fir, echinacea, chamomile, thistle, eleutherosis, periwinia, eleaf, eleutherosis, elene, eleutherosis, garland, eleutherosis, eleaf, eleutherosis, eleaf, English walnut, English yew, ephedra, EGCG (epicatechin gallate), willow herb, salix floribunda, epimedium herb, equ a, equisetum, calciferol, yerba eriodictyon, oriental coppera, Eschschschschschscholtzia, escoba negra, espirulina, essiacestevia, eucalyptus oil, efobio, eufrasia, clove, eupatorium perforatum, euphorbia, euphorbiaceae, eyeweed, cranberry, acai berry, evening primrose oil, evodia rutecarpa, eyeweed, buckwheat, fennel (fennel), fenugreek, fermented milk, ferula asafetida, compositae, fig, ficus insipida, fig, Filipeda, Filipendula ulmaria, weeds, flaxseed and linseed oil, sweet phosphorus-soda, fast enema, flor-scienceToad bacteria, fleece-flower root, digitalis, strawberry, wild strawberry, longan, cascara sagrada, frankincense, fraxinus, French rose, aconite root (common monkshood root), frutus barbarum, sea oak, strengthening body resistance and detoxifying soup, gallic acid, galangal, snowflower, Angustifolia bark, axanthus, gallimum aparine, winged euonymus, ganoderma lucidum, garcinia tenuifolia body, honey-fried dough, and the like,Mangosteen, garcinia, a cido hidroxic acid, garlic, garra del diablo, animal glue, gelidium, jasminum, genistein, gentian violet, geranium, chamomile, stachys, germario, germanium, germania, malt, polygonum cuspidatum, gimnema, gentian, ginger, ginkgo tree, ginseng, red sage, artichoke, wild soybean, glycyrrhiza glabra, goya, sythia, kava, goldenseal, goldenseflower, goldenseal, caraway, asiatic centella, gossypol, gotu kola, francci, caracia, caraway, pea, caraway, pea, caraway, pea, caraway, orange, pea, caraway, pea, guarana, guayule, viburnum, guggals, ghatti, gum arabic, acacia, gelsemium, guru, gymnema, gynostemma pentaphyllum, hamamelis, hange koboku-to, haritaki, devil's claw, cannabis sativa, hawthorn, hazelnut, spearmint, ivy, sunflower, dodder, hemlock, hempseed oil, swertia, pubescent angelica, hesperidin, hibiscus, hiedra terrestre, hierba bacterium, hierba de cabra cell (epimedium), hierba de lim n (citronella), hierba san junan (weeping forsythia, hierba de trigo (wheat), shrubby raspberry, sea buckthorn extract, holy basil, hochu-eki-to, honey, honeysuckle, hongo, sarsa, peppermint, hemlock parsley, mukutaenia extract, chinese mukuri, chinese mukutah, chinese hol, meadow, chinese chestnut, chinese arborvita seed, barnacre, hol seed, holbokutah-oki-o, mange, mangosteen, mangrove seed, mange seed, mangrove, Astragalus membranaceus, huang-teng ken, hops, huperzia serrata, huperzine a, hyaluronic acid, hydrangea aspera, goldenseal, hydrazine sulfate, asiaticoside, blumea balsamifera, hypericum perforatum, hypoxis hemerocalli, African potato, peppermint, ignacia (or strychni ignatii), star anise, impatiens balsamina, impatiens palatanta, mandarin orange, tilleria indica, fig, abrus, canthus plant, green reed canary, Indian snake root, ramose groundsel herb, inula caulana, elecampane, ipecactus, yam, ipomoea officinalis, eupatorium japonicumPurplavone, Iris pallida, Isatis root, iscador, ispagula, ivy, jackfruit, Picraenaceae, Taxus japonica, Japanese sophora, jasmine, ginger, red bean, jervine alkaloids, impatiens of Balsaminaceae, recipe for invigorating spleen and warming kidney, Gynostemma pentaphyllum, Datura, Christina, jojoba oil, yucca, walnut, juniper, kan jangKaraya gum, karkakada, katuka, kale, kava (piper methysticum), kefir, kelp, arabic tea (catha edulis), amitraz (acerola, also known as vesamine), kinetin, kiwi fruit, hypericum nigrum, kola, korean ginseng, kojic biotin, coriolus versicolor polysaccharide, krill oil, kudzu, labdana tea tree, lactalbumin, lactobacillus acidophilus, lactobacillus rhamnosus, lactobacillus plantarum, lactobacillus reuteri, lactobacillus, lactobacilli acid filo, lactoferrin, lupulus, cypripedium, amygdalin, lagerstroe, lagerstroemia, larch arabinogalactan, larch, quercus, amaranthus, laurus persea, lapisea, lavender, lecithin, lilac, lemon balm, olive, kom, kola, ko, Lentinus edodes, Rinderstoceae, leonurus, vicia adenophora, lepidium peruvianum chac Lou, Chelidonium majus, Alpinia officinarum, lessertia frutescens, Angelica gigas, L-glutamine, lichen, Glycyrrhiza glabra, lignans, Ligustrum lucidum, Citrus aurantium, Tilia marianii, bilberry, linseed oil, flax, lipolytic enzymes, lirio azul, lirio de aga blanco, liverwort, L-norvaline, Lobelia inflata, locust bean, lomatium, lomatidium dispum, Piper longum, Caprifolium, magic root, lorenzo's oil, lotus, Maria, Leptophyra, Lucky grass, lucky nut, bamboo shoot pustus, Ginseng, lute interface, tomato, Pinus sylvestris, Mitsumadia, Schizophylla, Schizophyllum chinensis, American ginseng, and so onMadagascar jewel, plants of the genus rubia (rubia cordifolia), basil, savory mint, magnolia and pinellia formulations, ginkgo biloba, grifola frondosa, malpidnia glabra, acerola, malva sylvestris, maltas malvasica, mangareca, citrus, mangosteen, manto de nuestra(Eschschschschschschschschschschschschschschschschschschlempe herb), Malus pumila, MAP30, Maranta arum, marigold, marrubio blanco, marrubium vulgare, hollyhock root, frankincense (psitacia lentisculus), chamomile, mauby bark, MCP (citrus pectin), meadowsweet, alfalfa, melaleuca alternifolia, melaleuca, melatonin, melissa officinalis, menaquilaria, microcrystalline cellulose, microcrystalline calcium, milenama, Muyuba, Silybum marianum, mistletoe, citrus pectin, Momordica charantia, Momordica grosvenori, Monascus, monascus purpureus, Aconitum, Morinda officinalis, morinda officinalis, Morus nigra, pistil, Oryza alba, peony, MSM (sagebrush), Artemisia spica, Murraya spicata, Murraya, Elaea, Elaeagnus, Murraya, Elaea, Moxifragrans, Murraya kol, Bay leaf, myrtle, myrrha, psyllium, watercress, neem, lotus, canceros, catnip, oleander, nettle, chondroitin, tabacum, tobacco, nigella, noni (morinda), nopal, zanthoxylum, pentanine, nuez de betel (betel nut), nutmeg, nux vomica, nymphae, oak bark, oak moss, oat beta-glucan, oat/grass, oat, basil, hollander, evening primrose, okra pod, sungloiopeltis, olea europaea, olibanum, olive leaf, olive oil, oly resbalandizo, american ginseng, opuntia, brazil palm oil, oregano grape, marjoram, ornithine, astaxanthin, hydroxyrutin tablet, bovine intestine pancreatin, bile extract, pacific tree, palm oil, palm oil (palma), palm oil palm oil, palm oil, palm oil, palm oil, Berbamba, ginseng, corn poppy, medicinal wall grass, parsley, parsnip, ginseng, corn,Guayule, parthenolide, plum blossom, passion flower, parsnip, pau D.C., bazedoary, baxixiang cocoa, sagnac, non-rubiaceae, PC-SPES, peanut oil, pectin, artemisia marjoram, petra hume ca (myrcia salicifolia), pelargonium, spearmint, peppermint (Mentha pulegium), peony, peppermint, perilla, catharanthus roseus, avocado, petasita, petasites, primrose, boldo, paorter, fexofenamine (navy bean), prunus quinata, mistletoe, phyllanthus, physalis somnifera, plant-1, striga, picraena, picrorhiza, spiure-bearing, pimentary, pimpinella, pinus sylvestris, kava sylvestris, kava sylvest, Plant esters, plantain, plantago lanceolata, plantago ovata, pleurisy, sinopodophyllum, plantago asiatica, poinsettia, poison ivy, poke, poleo americana, policosan, policosanol, polygonum cuspidatum, polygonum multiflorum, hylocereus orientalis extract and anapsos, pomegranate, poplar, poppy flower, margaria, zanthoxylum bungeanum, prickly ash, primrose, primula flower, nona huana, proteta, primrose, propolis, selfheal, africana plum, almond oil, apricot, plantain, muira brazil, pueraria root, menna variable pueraria root, puerarin, phlorogin, pulegone, pulsatilla, pumpkin seed oil, plantago, prunus salicina, pyrus indica, pyrrosia acetonide, artemisia, artemisinin, kennel, ketoquassia, royal jelly, japanese arborvitae, and royal jelly (quebrachium), japanese kombu, royal jelly, mangiferous plant (Royale, Royales) extract, mangiferous extract, Japanese pepper, and royal jelly, Spiraea villosa, Lagerstroemia speciosa, white oak, oak bark, Urtica fragaria, quick-in-the-hand (impatiens, Balsaminaceae), quimsa-kuchu, quinoa, quinsu-cucho, thatch, rabdosia, radium weed, Angelica sinensis, ranicuus bulbosus, Ranunculus ficus, rapeseed oil, Rubus idaeus, Serpentis wood, Rhodophyta, red clover, red palm oil, red sorrel, African plum, red kojic rice, licorice wine, rehmannia glutinosa, spiraea ulmaria, Ganoderma lucidum, rennin, Hippocampus japonicusPlum, rhubarb, palmate rhubarb, rhodiola, ice rhodiola, ledum palustre, petiole of rhubarb, poison ivy, ribes nigrum, rice bran oil, rilkole, rose blanco, roman chamomile, Roumeluo, loevigata, dog rose, hen bead, rose haw, rose hip, rose bay, roselle, chrysanthemum, rosemary, royal jelly, yellow, blackberry, raspberry, downy raspberry, ruibarbo, rumalon, butcher's broom, ruta, rutin, ryegrass, saw palmetto, slya bila, yeast for wine, salvia, safflower, grass, saikoku-to, bupleurum liver-clearing soup, salbaPopulus alba, Salix alba, Salvia officinalis, Spanish Salvia, Salvia officinalis, Salvia muricata, Salvia miltiorrhiza, Salvia officinalis, Cymbaria bassiana, sambucas nigra, Santalum album, sanguinarine, Santalum album, sassafras, elderberry (sambucus nigra), Serenoa serrulata, Schisandra chinensis, Schisandracea, Schizopeta, hyoscyamine, sparrow flower, Scutellaria lateriflora, Scutellaria barbata, Scutellaria lateriflora, Hippophae rhamnoides, Fucus vesiculosus, Gymoschata, Seerage, hydrazine sulfate, Stichopus japonicus, pinostrobin, sennosine, Serenoa serrulata, sesame oil, SesoChaceivigetotal, shakuyaku-kanzo-to, shallot, Muscovy, shark cartilage, shepherdspurse herb, Alternanthera, Alternaria, Sinopoda, Populus, Potentilla fragaria, Sinomenium, Berberidis, Melissimalia marianum, Melaleucaria, Melissa officinalis, Elm, smilax china extract, smokeless tobacco, ophidian, viburnum, soybean, solidago, sophorae, sorghum, palmate rhubarb, tart cherry, lime juice, soybean extract, soybean bran, soybean protein, soybean sprout, soybean oil, sparteine, spinach, germanospironine, spirulina, daphne giraldii, shallot, Igongdong, carob, hypericum, stachys, japonicas, illicium verum, goosegrass, karaya, stevia rebaudiana, stingleleburr, stinging nettle, stink gooseberry, strychnos, sophora japonica, substance x, sulfto de conduritina, brazil ginseng (fabaceae), sunflower seed, etcOil, Satherland diya shrub, sneeze root grass, sweet almond, sweet orange, licorice, common clover, sweet wormwood, Acorus calamus, comfrey, kangfujin, stink, Tongluoling, tamarind, black sprawl, chrysanthemum, orange, chrysanthemum, dandelion, taurine, tea tree oil, tejo, Terminalia, European bitter grass, cacao, yellow oleander, oriental arborvitae, thunder god vine, thyme (thymus vulgaris), medlar, tilofora, toki-shuyaku-san, poison ivy (eastern poison ivy), tragacanth, pink tobacco, Chinese poplar, tribulus terrestris, Brazilian sea seed oil, red clover, fenugreek, Trigonella foenum-graecum, Trimethylethanolamine, centella asiatica, wheat, Canadian catharanthus canadensis extract, total sessile extract, turmeric, total sessile grass extract, turmeric, tussilagra, turmeric, Tripterygium sinensis, Trifolium oryzae, Tripterygium officinale, Trifolium, Tripterygium officinale, Trigonellae, terna grass, turpentine, coltsfoot, tylophora indica, ukrain^TMUlmus/ulmus, amorphophallus, Uncaria tomentosa, Allium fistulosum, nettle, Usnea barbata, Arctostaphylos uva-ursi, bilberry extract, valerian, hairy antler, Flora villosa, Potentilla vulgaris, Verbascum serrulata, Verbena officinalis, Phlebia macrophylla, vetiver (chrysogenin zizanoides), hydrangea macrophylla, Crataegus oxyacantha, vinagrre de sidra de manzana, Vinca minor, vinpocetine, Cirsium japonicum, virginia's herbal E-Tonic^TMWhite mistletoe, negundo chastetree, grape pip, white quinoa, wasabi, parsley, watercress, wheatgrass, wheat bran/grass, malt, wheat malt, lactalbumin, white bean cotyledon, mallow, white oak, white pepper, white sandalwood, white tea, white water lily, wildarch, wild carrot, wild cherry, wild ginger, indigotin, marjoram, wild rosemary, wild yam, willow bark, witch hazel, winter cherry, wintergreen, red sage, red-striped meadow rue, western snow fruit, wormwood, xangoXanthan gum, Xanthomonas campestris, Xhoba, radix Panacis Quinquefolii, picrorhiza scrophulariiflora Pennell, Mesona chinensis Benth, herba Epimedii, xianxaxao, Xiaoqinglong decoction, Xiaochaihu decoction, xukucao, Xukucao, Yuzhu, yagonaYam, mushroom, waxberry, kava, yangana, yarrow, licorice, yashti madhuka, yavatikta, yege, yellow clover, yellow beeswax, yellow beet, canary flower, rumex crispa, yellow ginseng, pongami, yellow lacquer, yellow indigo, yellow jasmine, oleander, yellow poppy, goldenseal, goldthread, sandalwood, yellowsaudus, elecampane, yemena myrrh, yerba duke, yerba mate, eriodictyon, yew, yi zhu, epimedium, yinhsing, yodo, yogaragugul gum resin, yohimbe bark extract (yohimbine), yona, huhu grass, yucca, aloe leaf yucca, yucca zelia, yucca brevian, yucca, small yucca, waya, yehou, yewa, pepper, etcGinger or ZMA^TM. The composition can be used as a nutritional supplement, a dietary supplement, a food supplement or as a food additive. The composition can be made into tablet, capsule, liquid, lyophilized powder, crystal, aerosol, liquid impregnated into skin patch, ointment or suppository.

In related embodiments, the magnesium counterion composition can also contain other nutritional ingredients including, but not limited to, calcium-containing materials (e.g., calcium carbonate), tin esters, hydroxycitric acid, vitamins, minerals, herbs, spices, and mixtures thereof. Examples of vitamins that may be used as additional ingredients include, but are not limited to, vitamin A (retinol), vitamin D (cholecalciferol), vitamin E group (alpha-tocopherol and other tocopherols), vitamin K group (phylloquinone and menaquinones), thiamine (vitamin B)₁) Riboflavin (vitamin B)₂) Nicotinic acid, vitamin B₆Folic acid, vitamin B₁₂(cobalamin), biotin, vitamin C (ascorbic acid) and mixtures thereof. The amount of vitamin or vitamins in the final product depends on the particular vitamin. Examples of minerals that may be used as additional components include, but are not limited to, calcium, phosphorus, iron, zinc, iodine, selenium, potassium, copper, manganese, molybdenum, and mixtures thereof. In the case of vitamins, the amount of minerals present in the final product depends on the particular mineral. It will be apparent to those skilled in the art that this list of other nutritional ingredients is provided by way of example only and not by way of limitation.

In addition to oral dosage forms, the compositions of the present invention can be administered to a subject by any useful and effective delivery system. Such delivery systems include, but are not limited to, dosage unit formulations for parenteral, transdermal, nasal, sublingual, transmucosal, intraarterial or intradermal modes of administration containing conventional non-toxic physiologically acceptable carriers, adjuvants and vehicles as required, for example, depot or controlled release formulations. Depending on the route of administration, the magnesium compositions of the present invention may be formulated as suppositories, lotions, patches or devices (e.g., subcutaneously implantable delivery devices or inhalation pumps). The composition may be optimized for a particular type of delivery.

In some embodiments of the invention, the magnesium and threonate are delivered in an aerosol spray formulation from a pressurized pack, nebulizer or dry powder inhaler. Suitable propellants which may be used in the atomiser include, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and carbon dioxide. In the case of a pressurized aerosol, the dose may be determined by providing a valve to deliver a prescribed amount of the compound.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable excipients as listed above. Preferably, the compositions of the present invention are administered by the oral, nasal or respiratory route to produce a local or systemic effect. The composition in an acceptable solvent may be atomized by using an inert gas. The nebulized solution can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask, a tent, or an intermittent positive pressure ventilator. The solution, suspension or powder composition may preferably be administered orally or nasally by means of a device delivering the formulation in a suitable form.

In some embodiments, for example, the composition can be delivered to the lamina cribosa nasally, rather than by inhalation, enabling delivery of the active agent from the olfactory pathway to the CNS, and reducing systemic administration. Devices commonly used for this route of administration are included in U.S. patent 6,715,485 entitled "Nasal delivery device". Compositions delivered by this route can increase CNS dose or reduce systemic burden, thereby reducing the risk of systemic toxicity associated with certain compositions.

The composition optionally can be formulated for delivery in a container, providing continuous, long-term delivery, e.g., up to 30 days, 60 days, 90 days, 180 days, or a year. For example, the container may be provided in a biocompatible material (e.g., titanium). The formulations for long-term delivery are particularly suitable for subjects with chronic conditions to ensure improved patient compliance and increased stability of the composition.

According to another embodiment, the composition of the invention is a liquid or semi-liquid comprising at least 20mg/L magnesium or at least 40mg/L magnesium. In some embodiments, the compositions of the present invention are liquids or semi-liquids comprising at least 5mg/L magnesium, at least 10mg/L magnesium, at least 20mg/L magnesium, at least 30mg/L magnesium, at least 40mg/L magnesium, at least 50mg/L magnesium, at least 60mg/L magnesium, at least 70mg/L magnesium, at least 80mg/L magnesium, at least 90mg/L magnesium, or at least 100mg/L magnesium.

Alternatively, the compositions of the present invention may be administered transdermally. Formulations for delivery in transdermal patches may be performed using methods known in the art, including those generally described in, for example, U.S. Pat. nos. 5,186,938 and 6,183,770, 4,861,800, 6,743,211, 6,945,952, 4,284,444, and WO 89/09051, all of which are incorporated herein by reference. The patch is particularly useful in embodiments where the active agent has absorption problems. Patches can be prepared to control the release of the skin penetrating active ingredient over 12 hours, 24 hours, 3 days and 7 days. In one embodiment, the 2 times the remaining amount of magnesium threonate a day is placed in a non-volatile fluid. A preferred release may be 12 to 72 hours.

In some embodiments, for example, the compositions can be delivered to the brain by nasal, buccal, or sublingual routes, rather than by inhalation, enabling delivery of the active agent to the CNS through the olfactory pathway, and reducing systemic administration. Devices commonly used for this route of administration are included in U.S. patent 6,715,485 entitled "Nasal delivery device". Compositions delivered by this route can increase CNS dose or reduce systemic burden, reducing the risk of systemic toxicity, e.g., diarrhea.

Preparation of compositions for delivery in a subcutaneous implantable device can be carried out using methods known in the art, such as those described in U.S. patents 3,992,518, 5,660,848, and 5,756,115. Other methods for preparing modified release formulations are described, for example, in U.S. Pat. nos. 5,422,123, 5,601,845, 5,912,013, and 6,194,000, which are all incorporated herein by reference.

Use of

The present invention provides methods of using the disclosed compositions. In some embodiments, the use comprises administering an oral dosage form of the present invention to provide various health benefits. Such compositions may comprise at least one magnesium counterion compound. The magnesium counterion compositions described herein can be used for any of the various applications and purposes described herein, such as maintaining, enhancing and/or improving the health, nutritional and/or other condition, and/or cognitive, learning and/or memory function of a subject. Magnesium deficiency may cause or be associated with a number of pathological conditions, such as loss of appetite, nausea, vomiting, fatigue, convulsions, cardiac dysrhythmias, diabetes and/or cardiovascular disease. According to several studies, magnesium deficiency may lead to or may be associated with attention deficit disorder (ADHD) and its associated symptoms in children (Kozielec et al, Magnes. Res.10(2), 143-148(1997) and Mousain-Bosc et al, Magnes. Res.19(1), 46-52 (2006)). The magnesium counterion compositions described herein may be used to administer to a subject suffering from magnesium deficiency, mild cognitive dysfunction, alzheimer's disease, attention deficit disorder, ALS, parkinson's disease, diabetes, migraine, anxiety, mood disorders, and/or hypertension, by way of example only.

Magnesium is an essential mineral for the human body and plays a role in many physiological functions. However, it is generally accepted that at least half of the population in the industrialized world do not receive sufficient magnesium from their diet. There are several diseases, such as diabetes and Alzheimer's Disease (AD), associated with magnesium deficiency. Therefore, magnesium supplementation is required. The recommended daily dose of magnesium for adults (RDA) is about 400 mg. Assuming that one obtains 40-50% of the magnesium required from the diet, it is recommended that the amount of magnesium supplement for adults is typically about 200-250 mg/day. There are many magnesium compounds used as magnesium supplements. These compounds include, for example, magnesium oxide, magnesium citrate, magnesium sulfate, magnesium chloride, magnesium gluconate, magnesium lactate, magnesium pyridonate, and magnesium diglycolate. Most commercial magnesium supplements recommend supplementation with about the same amount of magnesium, at least for nutritional purposes (i.e., about 250mg magnesium/day), regardless of the bioavailability of the magnesium compound and the renal function of the individual in retaining the amount of magnesium absorbed. Some suppliers of magnesium supplements recommend higher daily magnesium intake for their products and still do not consider the renal function of individuals that retain magnesium. Similar to magnesium deficiency, excess magnesium in the body (hypermagnesemia) can also lead to health problems such as neuromuscular depression (neuromusculature depression), hypotension, cardiac arrhythmias, and respiratory paralysis. Therefore, it is important to keep blood magnesium levels within the normal range. Disclosed herein is a novel method for controlling magnesium levels to specific regions of the normal range. In some aspects of the invention, the methods also provide specific health advantages, such as increased memory, increased longevity, reduced depression, and reduced symptoms of neurological disorders, including AD.

In addition to its nutritional use, magnesium supplements are also used to treat type 2 diabetes. In one study, diabetic patients were treated with approximately 1g of magnesium per day for 1 month (de Lordes Lima, et al, diabetes Care.21: 682-6 (1998)). This treatment increased the magnesium levels in the patient's serum by about 10%, but only slightly improved metabolic control. In another study, diabetic patients were treated with 720 mg/day magnesium for 3 months. Also, the blood magnesium levels in patients are increased by an average of about 10% (Eibl, et al, Diabetes Care.21: 2031-2 (1995)). However, there was no improvement in metabolic control assessed with patient HbA1c levels.

Magnesium ions have been reported to be commonly used in the treatment of dementia (e.g., U.S. patent 4,985,256 entitled "Methods for diagnosing, monitoring and controlling the onset and progression of dementia and predicting memory loss or predicting impact of memory"). Landfield and Morgan demonstrated that young (9 months old) and old (25 months old) rats showed some signs of improvement in cognitive function 8 days after feeding food containing 20% magnesium oxide (Landfield and Morgan, Brain Research, 322: 167-. However, acquisition of cognitive function is temporary and the animals pay the cost of diarrhea and weight loss. In fact, since the side effects were so severe, researchers had to use an alternative feeding regimen, administering the animals a high Mg diet for 4 days, followed by a 2 day regular diet, and then returning to the high Mg diet for an additional 4 days.

Magnesium compounds may also be used to affect bone density. Abnormal bone density, including but not limited to osteoporosis, can be treated by supplementation with the magnesium compounds of the present invention. Treatment of a subject may ameliorate the effects of low bone density or as a prophylaxis against loss of bone density. Bone density can be determined by any means known in the art including, but not limited to, dual energy X-ray absorptiometry (DEXA), ultrasound, quantitative computed tomography, single energy absorptiometry, magnetic resonance imaging, measurement of metacarpal width, and hand X-ray diffraction analysis.

As described above, the magnesium counterion compositions and/or methods described herein can be used for a variety of purposes, such as maintaining, enhancing and/or improving the health, nutritional and/or other condition, and/or cognitive, learning and/or memory functions of a subject. Examples of such conditions in a subject include magnesium deficiency, mild cognitive dysfunction, alzheimer's disease, huntington's disease, autism, schizophrenia, cognitive decline as a side effect of a disease or medical treatment (HIV disease, cancer, chemotherapy), depression, senile dementia, attention deficit disorder, Amyotrophic Lateral Sclerosis (ALS), parkinson's disease, diabetes, cardiovascular diseases (such as hypertension), glaucoma, migraine, anxiety, mood, and hypertension, to name a few. Magnesium supplements may also be used to maintain, enhance and/or ameliorate conditions caused by the body's loss of magnesium, including but not limited to, alcoholism, anorexia, bulimia, metabolic syndrome, and malnutrition. Any such condition can be considered or defined as, for example, a pathological, psychiatric, physiological or medical condition or disorder. In general, the term "subject" may refer to any animal. Examples of such animals include, but are not limited to, cold blooded animals, warm blooded animals, mammals, domesticated mammals, primates, humans, and the individual or patient to whom the composition is administered is for experimental, diagnostic, nutritional and/or therapeutic purposes. The subject or patient may be one whose health, mood, cognitive, and/or nutritional status is normal, good, or excellent, or one whose health, mood, cognitive, and/or nutritional status is impaired, including abnormal, weak, impaired, unhealthy, impaired, diseased, and/or nutritionally deficient. The subject may be of any age, including the elderly.

In general, the term "cognition" refers to the process of obtaining, organizing, understanding, processing, and/or using information or knowledge. In general, enhancing cognitive function refers to enhancing any aspect of such processes, such as learning, performing psychological activities, storing, retrieving and/or using information and/or ideas, memory, and/or preventing deterioration of a subject's cognitive state. Various standard tests can be used to assess cognition, cognitive function, and/or cognitive status, and can be used to identify subjects who may contribute to, benefit from, and/or need to maintain and/or enhance the same and/or monitor the same therapeutic effect. Examples of suitable assays include the mini-mental state test (Folstein, 1975), the PROSPER neuropsychological test battery pack (Houx, 2002), and the like. Family history, age, and/or other factors may also be used to identify subjects who may benefit from, and/or need to maintain and/or enhance cognitive, cognitive function, and/or cognitive state.

Generally, the term "co-administration" with respect to two or more subjects used to administer, for example, a component, agent, substance, material, composition, etc., to a subject's body refers to administration using a dose and a time interval such that the subjects appear together within the subject's body or at the site of action in the subject's body within less than a minimum amount of time interval. The time interval may be any suitable time interval, such as a suitable minute, hour, day or week interval. The subjects of administration may be administered simultaneously, e.g., as part of a single composition or otherwise. The subjects may be administered at about the same time (e.g., less than or equal to about 5 minutes, about 3 minutes, or about 1 minute from each other) or within a shorter time of each other (e.g., less than or equal to about 1 hour, 30 minutes, or 10 minutes from each other, or greater than about 5 minutes to about 1 hour). The subjects administered in this way can be considered to be administered at approximately the same time. One of ordinary skill in the art can determine an appropriate dose and time interval for administering the subject to the body of the subject such that the subject is present at greater than a minimum level and/or at an effective concentration in the body of the subject. When the subjects are co-administered to the body of the subject, any subject can be in an effective amount that is less than the effective amount used for its individual administration. The term "effective amount" is further described herein and encompasses less than an effective amount and generally an effective amount, as well as an amount that is effective in actually causing a particular condition, effect and/or response. For this reason, the dosage of such co-administered subjects may be less than the dosage used when they are administered alone. One or more of the effects of any such subjects may be additive or synergistic. Any such subject may be administered at more than one time.

Generally, the term "effective amount" with respect to an active agent refers to an amount of the active agent sufficient to elicit a particular biological condition, effect and/or response. The absolute amount of a particular agent that is effective in this manner depends on various factors, such as the desired biological endpoint, the agent itself, the subject or the portion thereof targeted, and the like. An effective amount of the active agent may be administered in a single dose or in multiple doses. Examples of biological conditions, effects, or responses that result from an effective amount of an active agent include maintaining and/or improving the behavior of a subject in a task involving or related to cognitive function, maintaining and/or improving the behavior of a subject in assays related to or related to cognitive function, maintaining and/or improving the rate of decline (e.g., slowing) of cognitive function, and the like. The components described herein can be in an effective amount or at least in an amount effective to render any of the particular objectives or purposes described herein relevant.

Generally, the terms "physiologically acceptable" or "pharmaceutically acceptable" refer to those biologically or pharmaceutically compatible for use in animals or humans, such as approved by a federal regulatory agency or a state government, or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The term "treating" as used herein in all its verb forms includes alleviating or ameliorating at least one symptom of a disease in a subject, including, for example, pain, alzheimer's disease, vascular dementia, or parkinson's disease. The term "treating" may refer to reducing or alleviating the intensity and/or duration of disease manifestation experienced by a subject in response to a given stimulus (e.g., stress, tissue damage, hypothermia, etc.). For example, for senile dementia, the term "treating" may refer to alleviating or alleviating a cognitive disorder (e.g., a memory and/or orientation disorder) or an overall dysfunction (daily living activity, ADL) and/or slowing or reversing a progressive deterioration in ADL or cognition. Within the meaning of the present invention, the term "treatment" also means preventing, delaying the onset (i.e. the period of clinical symptoms of the disease) and/or reducing the risk of development or worsening of the disease. The term "protect" as used herein refers to the prevention, delay or treatment, or the development or continuation or exacerbation of disease in all subjects, as appropriate. Within the meaning of the present invention senile dementia is associated with CNS disorders including, but not limited to, neurodegenerative diseases such as Alzheimer's Disease (AD), down syndrome and cerebrovascular dementia (VaD). The term "treatment" includes the actions of "treating" described above.

The term "dose-proportional" as used herein refers to the relationship between the dosage of an active ingredient and its bioavailability. For example, if the dose ratio is twice that of the same composition, then twice as much active ingredient will be delivered and provide the same bioavailability (e.g., AUC) as one dose of the dosage form. The dosage ratios of the present invention are applicable to a wide range of dosages as discussed in detail herein.

Generally, the term "elemental magnesium" used in connection with the magnesium counter-ion compounds described herein refers to the total amount of magnesium present as free ions and bound to one or more counter-ions. In general, the term is not intended to refer to magnesium associated with a substance other than a magnesium counterion compound, which may be an ingredient of a magnesium counterion composition (e.g., a pharmaceutical composition, a dietary supplement composition, a food supplemented with a magnesium counterion compound). Small amounts of magnesium may be naturally present in or associated with such materials. For example, juice extracts or flavors may contain a portion of naturally occurring magnesium derived from fruit. Generally, the term "elemental magnesium" as used in connection with magnesium counter-ion compounds does not include magnesium in connection with such species.

As used herein, the terms "magnesium-containing component" (MCC) and "magnesium counterion compound" are used interchangeably and may be used for purposes described herein, e.g., to maintain, enhance and/or improve the health, nutrition and/or other condition of a subject, e.g., magnesium deficiency, diabetes, mood, attention deficit disorder, ALS, parkinson's disease, anxiety, depression and/or migraine, and/or cognitive, learning and/or memory functions, such as MCI and/or AD.

Magnesium threonate has been shown to have the highest bioavailability compared to magnesium compounds that are commonly used as magnesium supplements. The ability to rapidly and efficiently deliver magnesium from the gastrointestinal tract to the blood makes this compound an excellent candidate for pharmaceutical applications, such as the treatment of neurological diseases or deficiencies associated with magnesium deficiency, or those for which magnesium is known to be effective. See U.S. patent application 12/054,373 entitled "magnetic compositions, Methods of Using Same, and Associated technology. For example, magnesium threonate has been found to be effective as a memory enhancer in young animals or in treating memory decline associated with aging or Alzheimer's Disease (AD) in animals. See U.S. patent application 12/054,373. However, for compositions to be used as dietary or nutritional supplements or for general health enhancement, there should be low side effects and provide health benefits. Unlike pharmaceutical compositions prescribed by health professionals for patients with specific medical conditions, dietary or nutritional supplements may be taken by healthy or unhealthy people and are generally on a daily basis for extended periods of time, such as months, years, or even a lifetime. Therefore, it is important to provide adequate data to support long-term safety and the benefits of dietary/nutritional supplements when the supplement is administered at an effective dose.

In some embodiments, the present invention provides a method of supplementing magnesium to a subject in need thereof. The subject may be any animal described herein. In some embodiments, the subject is a human. Immediate release formulations of Magnesium threonate (and related compositions) have proven useful in a number of settings, including improved Cognitive Function and synaptic plasticity (U.S. patent application 12/054,367 entitled "Magnesium compositions and Uses Thereof for Cognitive Function" and 12/258,891 entitled the same), treatment of Neurological diseases (U.S. patent application 12/054,384 entitled "Magnesium compositions and Uses Thereof for Neurological Disorders"), treatment of Metabolic Disorders (U.S. patent application 12/054,374 entitled "Magnesium compositions and Uses Thereof for Metabolic Disorders"), and extended longevity (U.S. patent application 12/054,368 entitled "Magnesium compositions and Uses Thereof for using lubricating Lispan").

The present invention provides methods of administering oral dosage forms. In some embodiments, a method of administering an oral dosage form described herein comprises administering the oral dosage form to a subject once a day (UID), twice a day (BID), three times a day, four times a day, or more than 6 times a day. In some embodiments, the oral dosage forms described herein are administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or seven times a week. In some embodiments, the oral dosage forms described herein are administered once a month, twice a month, three times a month, four times a month, five times a month, six times a month, or more than six times a month.

The oral dosage forms described herein may be used to supplement magnesium in a continuous manner, e.g., for life. The dosage form may also be used to provide magnesium over a period of time, such as a period of time sufficient to treat, control, or otherwise benefit magnesium deficiency. In one embodiment, the present invention provides a method of supplementing magnesium to a subject in need thereof, the method comprising administering to said subject an oral dosage form as described herein at least twice a day for a period of 1 month or more, 2 months or more, 3 months or more, 4 months or more, 5 months or more, 6 months or more, or at least twice a day for a period of 1 year or more. In some embodiments, once a day administration is sufficient to provide optimized magnesium supplementation.

Using any administration regimen, such as those described herein, the present invention provides methods of treating a disorder associated with magnesium deficiency, comprising administering to a subject in need thereof any oral dosage form described herein. For example, the condition may be a neurological disease, cardiovascular disease or metabolic disorder. Other conditions that would benefit from the present invention include, but are not limited to, magnesium deficiency, mild cognitive dysfunction, alzheimer's disease, attention deficit disorder, ALS, parkinson's disease, diabetes, migraine, anxiety, mood disorders, and/or hypertension. It will be appreciated by those skilled in the art that the oral dosage forms and methods of the invention may be used to treat any condition that responds favorably to magnesium supplementation.

In other embodiments, the oral dosage form of the invention is administered to a subject at a dose of about 4mg elemental magnesium/kg/day to about 8mg elemental magnesium/kg/day, or from about 2mg elemental magnesium/kg/day to about 12mg elemental magnesium/kg/day, or from about 2mg elemental magnesium/kg/day to about 10mg elemental magnesium/kg/day, or from about 4mg elemental magnesium/kg/day to about 12mg elemental magnesium/kg/day, or from about 6mg elemental magnesium/kg/day to about 12mg elemental magnesium/kg/day, or from about 2mg elemental magnesium/kg/day to about 10mg elemental magnesium/kg/day, or from about 4mg elemental magnesium/kg/day to about 10mg elemental magnesium/kg/day, or from about 6mg elemental magnesium/kg/day to about 10mg elemental magnesium/kg/day. The optimal dosage depends on the subject. In some embodiments, the subject is a human. In this embodiment, the dosage can be optimized for treating a condition in a human.

In some embodiments, the oral dosage form of the invention is administered to a subject at a dose of less than about 2mg elemental magnesium/kg/day, less than about 4mg elemental magnesium/kg/day, less than about 6mg elemental magnesium/kg/day, less than about 8mg elemental magnesium/kg/day, less than about 10mg elemental magnesium/kg/day, less than about 12mg elemental magnesium/kg/day. In some embodiments, the oral dosage form of the invention is administered to a subject at a dose of greater than about 2mg elemental magnesium/kg/day, greater than about 4mg elemental magnesium/kg/day, greater than about 6mg elemental magnesium/kg/day, greater than about 8mg elemental magnesium/kg/day, greater than about 10mg elemental magnesium/kg/day, or greater than about 12mg elemental magnesium/kg/day. The optimal dosage depends on the subject. In some embodiments, the subject is a human. In this embodiment, the dosage can be optimized for treating a condition in a human.

In some embodiments, the present invention provides an oral dosage form comprising magnesium (Mg) and threonate (T), wherein said threonate comprises one or more of a threonate salt or a threonate precursor, wherein said oral dosage form is susceptible to absorption or retention upon administration to a subject, such that at least about 50% of said administered magnesium is absorbed by said subject, or at least 30% of the magnesium administered to the subject is retained for at least two days, when said oral dosage form is administered at a dose of 20 Mg/kg/day or higher.

The magnesium form described herein is highly advantageous for its high bioavailability. The administration regimen and the dosage administered depend on the amount of magnesium bioavailable to the subject. In some embodiments, greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or greater than about 90% of the administered magnesium is absorbed in the subject.

In some embodiments, the amount of magnesium absorbed by the subject is proportional to the dose. For example, the amount of magnesium absorbed is linearly proportional to the dose. In some embodiments, when the oral dosage form is administered to a subject in an amount of from about 20 mg/kg/day to about 100 mg/kg/day, or from about 20 mg/kg/day to about 90 mg/kg/day, or from about 20 mg/kg/day to about 80 mg/kg/day, or from about 20 mg/kg/day to about 70 mg/kg/day, or from about 20 mg/kg/day to about 60 mg/kg/day, or from about 20 mg/kg/day to about 50 mg/kg/day, or from about 30 mg/kg/day to about 100 mg/kg/day, or from about 40 mg/kg/day to about 100 mg/kg/day, or from about 50 mg/kg/day to about 100 mg/kg/day, or from about 60 mg/kg/day to about 100 mg/kg/day, or about 70 mg/kg/day to about 100 mg/kg/day, shows an increase in absorbed magnesium in proportion to the dose.

In some embodiments, the dissolution rate of magnesium in a dosage form of the invention is about 40-80% in about 6 to 10 hours.

Magnesium compositions may cause diarrhea. Indeed, magnesium compounds are commonly used as laxatives, and magnesium hydroxide is a commonly known over-the-counter laxative, which is the active ingredient of Phillips' Milk of Magnesia. Furthermore, chinese patent 1200366a discloses the use of magnesium threonate as a laxative. However, the present invention shows that magnesium threonate in a number of common magnesium supplement compounds has a minimal tendency to cause diarrhea. See example 2 and figure 1.

The incidence of diarrhea can be assessed by: a dose of magnesium threonate or a precursor thereof is provided to a group of test animals (e.g., rats or mice) and the group of animals is evaluated for the incidence of diarrhea. In one embodiment, the present invention provides an oral dosage form comprising from about 30Mg to 2000Mg magnesium (Mg), wherein the oral dosage form is a controlled release formulation, and wherein upon administration of greater than 40 Mg/day of the oral dosage form to a subject, an incidence of diarrhea of less than 20% results. The incidence of disease depends on the particular subject, the subject's weight, and the bioavailability of the magnesium provided. For example, the incidence of diarrhea in mice fed an aqueous solution of magnesium threonate depends, for example, on the ancestry, age, or sex of the mice.

In some embodiments, the oral dosage form of the invention, when administered at a dose greater than 80 mg/day, provides a diarrhea incidence of less than 50%, 40%, 30%, 20%, 10%, or less than about 5%.

In some embodiments, the incidence of diarrhea is less than 20% when administered to a subject at a dose greater than 40 mg/day for at least about 2, 3, 4, 5,6 days. In some embodiments, the incidence of diarrhea is less than 20% when administered to a subject at a dose of greater than 40 mg/day for at least about 1 week, or 2 weeks, or 3 weeks or more. In some embodiments, the incidence of diarrhea is less than 20% when administered to a subject at a dose greater than 40 mg/day for at least about 1 month.

The high bioavailability of magnesium threonate relative to other forms of magnesium is shown in fig. 2A and B. For example, the most widely used magnesium supplement, magnesium oxide, has been reported to have a bioavailability of only 4% (Ranade VV, Somberg JC. Bioavailability and pharmacological science of magnesium after administration of magnesium salts to humans. Am J Ther.2001 Sep-Oct; 8: 345-57). Thus, subjects who take the same recommended amount of elemental magnesium using magnesium threonate for a long period of time show higher, previously unexpected blood magnesium levels than other magnesium supplements. Magnesium threonate also provides superior in vivo magnesium retention. Figures 2C and D show that, despite its maximal absorption of magnesium, magnesium threonate has a similar rate of excretion of blood magnesium through urine as other magnesium compounds. Therefore, magnesium threonate is higher than other magnesium compounds in determining the magnesium retention rate (absorption rate-excretion rate) of the final bioavailability of magnesium compounds. Thus, this makes magnesium threonate the most effective compound for increasing magnesium levels in tissues and other body fluids at present. Indeed, magnesium threonate significantly increased the magnesium level in the mouse brain (i.e. the concentration of magnesium in the cerebrospinal fluid (CSF)) 24 days after treatment, whereas magnesium chloride and magnesium gluconate in milk had relatively limited effects (fig. 3). These data indicate that threonate generally promotes the entry of magnesium into the brain. This increase in magnesium in the brain is consistent with an improvement in cognitive function in the animal. See U.S. patent application 12/054,373 entitled "Magnesium composition, Methods of Using Same, and Associated technology.

Accordingly, the present invention provides a method of increasing magnesium in the central nervous system of a subject comprising administering to the subject an oral dosage form as described herein. In some embodiments, the oral dosage form comprises a controlled release form of magnesium (Mg) and threonate (T), wherein said threonate comprises one or more of threonate or a threonate precursor. In some embodiments, administration of the oral dosage form provides an increase in magnesium concentration in the cerebrospinal fluid of the subject, wherein the increased magnesium concentration in the cerebrospinal fluid of the subject is from about a 5% increase to about a 10% increase after about 10 days compared to baseline without administration of magnesium. In some embodiments, the increased magnesium concentration in the cerebrospinal fluid ranges from about 1% to about 10% increase, or from about 2% to about 10% increase, or from about 3% to about 10% increase, or from about 4% to about 10% increase, after about 10 days of administration of the oral dosage form. In some embodiments, the increased magnesium concentration in the cerebrospinal fluid of the subject is an increase of about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or more, or an increase of about 10% or more after about 10 days.

The compositions of the present invention can provide such high levels of magnesium without adverse effects. In some embodiments, compositions are provided that have an adverse effect for at least 1 month, 2 months, 3 months, 4 months, 5 months, or at least 6 months. In some embodiments, compositions are provided that have an adverse effect for at least 1 year, or 2 years, or 5 years, or 20 years, or lifetime. For example, magnesium threonate is used for the remainder of the life of normal male and female mice aged 15 months. See example 4. The results show that animals treated with magnesium had a normal lifespan (figure 4). In these experiments, the daily dose of magnesium (75 mg/kg/day) was in an amount corresponding to an effective dose for enhancing memory in normal young and aged mice as well as in short term magnesium treatment experiments in AD mice. See U.S. patent application 12/054,373, "Magnesium Compositions, Methods of Using Same, and any of the several technologies". The data indicate that magnesium threonate has no long-term toxicity when used at physiologically effective doses.

The oral dosage forms of the present invention further provide health benefits against a high calorie diet. In the experiment, the compound was administered to mice that were 10 months old and whose rest lives were on a high calorie diet. As expected, the group of animals with a high calorie diet plus magnesium threonate, as well as the group of other animals with a high calorie diet but without magnesium threonate (control #1), both increased significantly with the intermediate weight (fig. 5A). Also as expected, the mortality rate of animals in the high calorie control group (control #1) was much greater than animals fed the standard mouse diet (control #2) (fig. 5B). However, animals with a high calorie diet plus magnesium threonate had a similar lifespan to animals with a standard diet. It is well known that a high calorie diet can lead to obesity, which in turn can lead to various health problems, including diabetes and cardiovascular disease. The results in fig. 5 indicate that magnesium threonate has a prophylactic effect on metabolic syndrome and other obesity-related health problems, thereby allowing the compound to be used for general health enhancement purposes in addition to being used as a magnesium supplement.

Obesity can lead to a number of serious complications. These include: type II diabetes, unhealthy cholesterol levels, heart disease (such as atherosclerosis, myocardial infarction, congestive heart failure, thromboembolism, sudden cardiac death, angina or chest pain), stroke, hypertension, sleep apnea, respiratory disorders, musculoskeletal diseases (e.g., osteoarthritis, back pain), gallbladder disease, fatty liver disease, cancer, asthma, chronic headache, varicose veins, deep vein thrombosis, coronary artery disease, gastroesophageal reflux disease (GERD), heartburn, depression, hernia, gallstones, urinary incontinence, irregular menstruation, infertility, and increased risk of pregnancy in mothers and children. Obesity can lead to premature death of many people.

In one embodiment, the present invention provides a method of maintaining a high calorie diet without significant risk of high calorie-related adverse effects, comprising administering to a subject an oral dosage form as described herein. In one embodiment, the oral dosage form comprises magnesium (Mg) and threonate (T), wherein threonate comprises one or more of threonate or a threonate precursor. The oral dosage form is effective in increasing the longevity of subjects on a high calorie diet. In some embodiments, administration of the oral dosage form to a subject on a high calorie diet results in protection such that the life span of the subject is comparable to the average life span of a medium weight subject.

In one embodiment, the invention provides an oral dosage form comprising magnesium (Mg) and threonate (T), wherein said threonate comprises one or more of threonate or a threonate precursor, wherein administration of said oral dosage form to a subject provides protection against high calorie dietary adverse effects in said subject. Adverse effects include, but are not limited to, atherosclerosis, heart disease, myocardial infarction, stroke, thromboembolism, metabolic syndrome, and diabetes. Various other complications of obesity are also disclosed.

The health-beneficial effects of the compounds of the present invention can be determined in a test animal, e.g., a rodent, such as a mouse or rat. See example 5. In some embodiments, the oral dosage form improves survival by at least about 10%, 20%, 30%, 40%, 50%, or more than 50% for such animals having a high calorie diet for at least about 60 weeks. In some embodiments, an increase in survival rate can be observed in a shorter time. In some embodiments, the oral dosage form increases survival by a significant amount for such animals having a high calorie diet for at least about 10 weeks, 20 weeks, 30 weeks, 40 weeks, or at least about 50 weeks. One skilled in the art will recognize how to determine the effect of survival, for example, using Kaplan-Meier survival curve analysis.

Kit III

The invention also provides kits for practicing the invention. The kit can include at least one component of any of the magnesium counter ion compositions described herein or any of the magnesium counter ion compositions described herein. In some embodiments, the kit comprises a magnesium threonate supplement in a controlled release oral dosage form or any variation described herein. In some embodiments, the kit comprises a bottle or other container holding the oral dosage form. In some embodiments, the oral dosage form is contained in a blister package to simplify the health and treatment regimen of the end user.

Examples

EXAMPLE 1 Process

Animals: adult male Sprague-Dawley rats were obtained from beijing vindolizhihua, china. Rats were housed individually in dwellings with freely available standard food and water, 12: 12h inverted light-dark cycle, and light was turned on at 8:00 pm. Once the bioavailability experiment was reached and started (below), rats were fed a commercial pellet feed containing standard magnesium (0.15%) and tap water ad libitum. All experimental procedures were approved by the animal care committee of the university of qinghua.

Treatment of different magnesium formulations: the following magnesium preparations were used in this experiment, magnesium threonate (Magceutics inc., usa), magnesium chloride and glycinate (Modern easter fine chemical, china), magnesium gluconate and magnesium citrate (Sigma-Aldrich, germany). Lactose was obtained from Biobasic Inc (beijing, china). To supply the animals with a dose of 50 mg/kg/day elemental magnesium, the following doses of each formulation were dissolved in the daily drinking amount: magnesium threonate (606 mg/kg/day), magnesium chloride (196 mg/kg/day), magnesium gluconate (853 mg/kg/day), magnesium citrate (310 mg/kg/day) and magnesium glycinate (355 mg/kg/day).

Determination of magnesium absorption, excretion and retention: rats were each housed in metabolic cages for 12 days during which time the animals received magnesium-free food. On days 4 to 10, animals received deionized water containing one of the tested magnesium compounds. From day 11 to day 12, rats were fed magnesium-free food and deionized water. During the magnesium supplementation period (day 4 to day 10), urine was collected from each rat every day, and fecal pellets were collected from day 5 to day 10. The collected urine and fecal pellets were pooled and the total volume of urine and total weight of feces collected for each rat were recorded. The pooled urine and fecal pellets from each rat were analyzed for magnesium content using inductively coupled plasma atomic emission spectrometry (ICP-AES) and the total magnesium content (mg) in the urine and feces was determined.

The percent absorption, excretion and retention was estimated by the linear regression slope of the following equation:

absorption ═ Mg_{Intake of}-Mg_{Excrement and urine})*100％/Mg_{Intake of}(equation 1)

Excretion of Mg_{Urine (urinary incontinence)}*100％/(Mg_{Intake of}-Mg_{Excrement and urine}) (equation 2)

Retention ═ Mg_{Intake of}-Mg_{Excrement and urine}-Mg_{Urine (urinary incontinence)})*100％/Mg_{Intake of}(equation 3)

Safety limits for different magnesium formulations: to evaluate the laxative properties of the different magnesium preparations, the animals were divided into 10 groups. Each group received a specific magnesium formulation at a dose of 15 to 138 mg/kg/day of elemental magnesium via drinking water. The amount of magnesium dissolved in the daily intake of water was determined on a basis of-30 ml/day/rat. The animals were supplied with magnesium-supplemented drinking water for 4 days, after which the number of animals with diarrhea per group was monitored and calculated as a percentage of the total number of animals.

Magnesium content in cerebrospinal fluid: animals in separate groups were evaluated for magnesium ion content in cerebrospinal fluid (CSF) at baseline (day 0) and on days 12 and 24 of treatment with different magnesium formulations. Animals were treated with various magnesium preparations at a dose of about 50 mg/kg/day elemental magnesium via drinking water. Before each sampling point, rats were anesthetized with chloral hydrate (400mg/kg, i.p.) and 50 μ l/animal CSF was manually taken from the cisterna magna by intervention of the atlantoaxial membrane with a microneedle of 450 μm diameter. CSF samples were collected and stored at-20 ℃ until magnesium determination. The level of magnesium was determined as described above.

Statistical analysis: all data were modeled with a normal distribution. Bioavailability analysis was performed using linear regression with 95% confidence intervals. To determine the 50% toxic dose (TD50) in animals, the best-fit nonlinear regression was analyzed using the variable Hill-slope with 95% confidence intervals. Cerebrospinal fluid data was analyzed using one-way analysis of variance. Data were analyzed using GraphPad prism (version 5.00, graphpadsofware Inc.). P values less than 0.05 were considered significant.

EXAMPLE 2 Effect of magnesium supplementation on the incidence of diarrhea

Figure 1 shows the incidence of diarrhea in rats fed various magnesium supplements. As the dose of magnesium was increased, the percentage of animals with diarrhea proportionally increased. At higher doses, magnesium threonate (MgT) is less likely to induce diarrhea. TD50 (toxic dose required to induce diarrhea in 50% of animals) for each compound was as follows: magnesium threonate: 131.5 mg/kg/day magnesium gluconate in milk (MgG + milk): 119.1 mg/kg/day, magnesium gluconate (MgG): 99.7 mg/kg/day, magnesium chloride (MgCl 2): 90.0 mg/kg/day. Magnesium compounds were added to the drinking water of rats to simulate the slow release of magnesium compounds as rats drink water over time.

Example 3 magnesium concentration in cerebrospinal fluid ([ Mg ]²⁺]CSF) increase

Mice were fed 24 days magnesium chloride (MgCl)₂) Magnesium gluconate in milk (MgG + milk) and magnesium threonate (MgT). FIG. 3 shows the concentration of magnesium ([ Mg ] in cerebrospinal fluid after treatment with different magnesium formulations²⁺]CSF). Magnesium threonate significantly increased the concentration of magnesium in the cerebrospinal fluid of mice after 24 days of treatment, whereas magnesium chloride and magnesium gluconate in milk had a relatively limited effect. Data were significant on day 24 using one-way ANOVA (p < 0.05).

Example 4 Effect of magnesium threonate (MgT) on longevity of animals fed normal diet

Male and female mice 10 months old were purchased from experimental animal technology ltd, beijing, vindolizhihua, china. Prior to the start of the experiment, mice were fed a commercial pelleted feed (shanghai slake laboratory animals ltd) containing ordinary magnesium (0.15%) and optionally tap water for 5 months. Four female mice were housed together in individual cages with a 12: 12h light-dark cycle with free access to food and water, with the light turned on at 8:00 a.m. Male mice were housed individually. At the start of the experiment, magnesium threonate (75 mg/kg/day elemental magnesium) was added to the drinking water of the mice. Survival curves were drawn using the Kaplan-Meier method, which included all available animals at each time point. 30 mice were used per group at the start of the experiment (fig. 4A and B).

Example 5 Effect of magnesium threonate (MgT) on longevity of animals fed a high calorie diet

Female mice 9 months old were purchased from Experimental animals technology, Inc. of Weitongli, Beijing, China. Prior to the start of the experiment, mice were fed 1 month with commercial pelleted feed (shanghai slake laboratory animals ltd) containing ordinary magnesium (0.15%) and optionally tap water. Four female mice were housed together in individual cages with a 12: 12h light-dark cycle with free access to food and water, with the light turned on at 8:00 a.m. At the beginning of the experiment, some mice were converted to a High Calorie (HC) diet by addition of hydrogenated coconut oil, providing 60% calories from fat (Baur et al, 2006Resveratro improves health and survival of micron a high-caloriee diet. Nature 444, 337-. A portion of HC-fed mice were supplemented with a MgT supplement of elemental magnesium at about 45 mg/kg/day via their drinking water. During the experiment, food intake and body weight were determined on a weekly basis. Survival curves were drawn using the Kaplan-Meier method, which included all available animals at each time point. 60 mice were used per group (i.e., normal diet, HC diet, MgT supplemented HC diet) at the beginning of the experiment (FIGS. 5A and B)

EXAMPLE 6 preparation of controlled Release tablets and Release Profile

To prepare a controlled release tablet, magnesium threonate is pulverized and sieved through a 80 mesh sieve. The magnesium threonate powder was mixed with 15% polyvinylpyrrolidone (PVP) in 95% ethanol, using 0.3mL 95% ethanol per gram of magnesium threonate powder. The resulting granules were sieved using a 12 mesh sieve to remove any unbound magnesium threonate. The granules were dried with pressurized air at 65 ℃ for 15 minutes and then sieved again using a 12 mesh sieve to remove any unbound debris. A pharmaceutically acceptable amount of magnesium stearate (5 mg per gram of magnesium threonate) was added as a lubricant to the dry granules. After thorough mixing, the lubricated granules were compressed into tablets of-1 g size. A coating solution was prepared by mixing 223.67g of 30% SR30D (polyvinyl acetate) (in water), 6.7g of polyethylene glycol and 19g of PVP, and then adding water to a total of 450 g. Pharmaceutically suitable amounts of lake dye and talc or titanium dioxide are also added to provide photoprotection and to facilitate the coating process. The resulting mixture was stirred well to form a homogeneous suspension. Coating the tablets by using the coating solution at 45-55 ℃ to obtain the controlled release tablets containing 1g of magnesium threonate and 70-90mg of auxiliary materials.

The release profile of the controlled-release tablet prepared above was measured in 250mL of physiological saline at 37 ℃ and a stirring rate of 75 rpm. The amount of magnesium released over time was determined by spectroscopy (Raymond J. Liedtke and Gery Kroon Clin. chem.30(11), 1801-1804 (1984)). The release profile is shown in table 1.

TABLE 1 magnesium Release over time

Time (h)	% released magnesium
		2	0
4	6.9
		6	32.5
8	60.1
		10	76.2
12	83.3
		24	104.6

The above data is plotted in fig. 6B.

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims (34)

1. An oral dosage form comprising magnesium (Mg) and threonate (T), wherein the threonate comprises one or more of a threonate salt or a threonate precursor, wherein the oral dosage form has an in vitro dissolution profile in a dissolution medium, and wherein the dissolution profile ranges from less than or equal to 5% within 2 hours, less than 10% within 4 hours, less than 40% within 6 hours, greater than or equal to 60% within 10 hours, and greater than or equal to 80% within 12 hours, when determined using a usp type II (paddle) dissolution system at a temperature of 75rpm and 37 ℃, wherein the threonate precursor comprises threonic acid, threonate ester, or threonate lactone.

2. The oral dosage form of claim 1, wherein said magnesium and threonate in said oral dosage form is encapsulated in a tablet.

3. The oral dosage form of claim 1, wherein at least a portion of said magnesium (Mg) and threonate (T) are MgT₂Complexation in the form of a salt.

4. An oral dosage form as claimed in any one of claims 1 to 3, wherein at least part of said magnesium (Mg) and threonate (T) is in MgT₂Complexed in the form of a salt and present in a weight amount equal to at least 20 Mg.

5. The oral dosage form of claim 1, wherein the molar ratio between threonate (T) and magnesium (Mg) is greater than or equal to 0.1 to 2.

6. The oral dosage form of one of claims 1 to 3, wherein the magnesium (Mg) is present in an amount of more than 1% by weight.

7. The oral dosage form of one of claims 1 to 3, wherein the magnesium (Mg) is present in an amount of more than 5% by weight.

8. The oral dosage form of one of claims 1 to 3, wherein the magnesium (Mg) is present in an amount of more than 7% by weight.

9. The oral dosage form of one of claims 1 to 3, wherein the magnesium (Mg) is complexed with an anion selected from chloride, taurinate, lactate, gluconate, citrate, malate, succinate, sulfate, propionate, hydroxide, oxide, orotate, phosphate, borate, salicylate, carbonate, bromide, stearate, amino acid, butyrate, aspartate, ascorbate, picolinate, pantothenate, nicotinate, benzoate, phytate, caseinate, palmitate, pyruvate and threonate.

10. The oral dosage form of any one of claims 1 to 3, further comprising a metal ion selected from the group consisting of calcium, potassium, sodium, chromium, iron, selenium, zinc, manganese, molybdenum, vanadium, and lithium.

11. The oral dosage form of one of claims 1 to 3, further comprising one or more antioxidants selected from resveratrol, ellagic acid, quercetin, lipoic acid, or vitamin C.

12. The oral dosage form of one of claims 1 to 3, wherein the dissolution profile is less than 5% in 2 hours, less than 10% in 4 hours, less than 40% in 6 hours, greater than or equal to 60% in 10 hours, and greater than or equal to 80% in 12 hours, when measured using a United states Pharmacopeia type II (Paddle) dissolution system at 75rpm and a temperature of 37 ℃.

13. The oral dosage form of one of claims 1 to 3, wherein at least 75% of the magnesium (Mg) and threonate (T) in the oral dosage form is provided in a controlled release dosage form.

14. The oral dosage form of one of claims 1 to 3, wherein at least 95% of said magnesium (Mg) and threonate (T) in said oral dosage form is provided in a controlled release dosage form.

15. The oral dosage form of one of claims 1 to 3, wherein 100% of said magnesium (Mg) and threonate (T) in said oral dosage form is provided in a controlled release dosage form.

16. The oral dosage form of any one of claims 1 to 3, wherein the dissolution medium is a saline solution.

17. The oral dosage form of one of claims 1 to 3, wherein the dissolution profile is zero order.

18. The oral dosage form of one of claims 1 to 3, further comprising a polymeric binder mixed with magnesium (Mg) and threonate (T).

19. The oral dosage form of claim 18, wherein the polymer comprises polyvinylpyrrolidone.

20. The oral dosage form of any one of claims 1 to 3, wherein the oral dosage form further comprises a pharmaceutically acceptable amount of magnesium stearate.

21. The oral dosage form of any one of claims 1 to 3, wherein the oral dosage form further comprises one or more of polyvinylpyrrolidone, polyvinyl acetate, or propylene glycol.

22. The oral dosage form of claim 1, wherein the threonate salt comprises one or more of a threonate salt or a threonate precursor, wherein the oral dosage form is effective to increase the lifespan of a subject on a high calorie diet.

23. The oral dosage form of claim 22, wherein administration of the oral dosage form to a subject on a high calorie diet results in protection such that the life span of the subject is comparable to the average life span of a subject of moderate weight.

24. The oral dosage form of claim 1, wherein the oral dosage form is administered to a human subject at a dose of 1mg elemental magnesium/kg/day to 16mg elemental magnesium/kg/day.

25. The oral dosage form of claim 24, wherein the oral dosage form increases survival by at least 40% for subjects having a high calorie diet for at least 60 weeks.

26. The oral dosage form of claim 1, wherein said oral dosage form comprises magnesium (Mg) and threonate (T), wherein said threonate comprises one or more of threonate or threonate precursors, and wherein said oral dosage form, when administered to a subject, provides an increased concentration of magnesium in the cerebrospinal fluid of the subject, wherein the increased concentration of magnesium in the cerebrospinal fluid of said subject ranges from a 5% increase to a 10% increase after 10 days of administration of said oral dosage form to said subject as compared to a baseline magnesium concentration without administration of magnesium.

27. Use of an oral dosage form as claimed in any one of claims 1 to 26 in the manufacture of a medicament for the treatment of a condition associated with magnesium deficiency.

28. The use of claim 27, wherein the condition is selected from the group consisting of neurological diseases, cardiovascular diseases and metabolic disorders.

29. Use of an oral dosage form of any one of claims 1-26 in the manufacture of a medicament for increasing magnesium in the central nervous system of a subject in need thereof.

30. Use of an oral dosage form according to any one of claims 1 to 26 in the manufacture of a medicament for maintaining a high calorie diet but lacking a significant risk of high calorie related adverse effects.

31. Use of an oral dosage form of any one of claims 1-26 in the manufacture of a medicament for supplementing a subject in need thereof with magnesium at least once daily.

32. Use of an oral dosage form of any one of claims 1-26 in the manufacture of a medicament for supplementing magnesium to a subject in need thereof at least twice daily for a period of 1 month or more.

33. A method of making the oral dosage form of any one of claims 1-26, comprising mixing a powder comprising magnesium (Mg) and threonate (T), wherein both magnesium (Mg) and threonate (T) are present in salt form, with a polymer in an amount sufficient to produce particles comprising magnesium (Mg), threonate (T), and polymer, wherein the particles have a size sufficient to be retained on a 12 mesh screen.

34. The method of claim 33, further comprising:

filtering the particles using a 12 mesh sieve to remove unbound threonate;

drying the granules;

adding a pharmaceutically acceptable amount of a lubricant to the particles;

compressing the granules into one or more pellets having a size of between 100mg and 2000 mg; and

coating the one or more pellets with a polymeric coating film comprising one or more of polyvinylpyrrolidone, polyvinylacetate, or propylene glycol.