Magnesium threonate compositions and uses thereof

Abstract

To provide dosage forms comprising magnesium threonate with enhanced efficacy.SOLUTION: Disclosed is a dosage form comprising magnesium threonate with enhanced efficacy for the treatment of a disease, disorder, syndrome, and / or condition in a patient in need thereof, where, (a) at least part of magnesium (Mg) and threonate (T) of the magnesium threonate is present in a salt form of MgT2; (b) the magnesium threonate is present in an amount between about 200 to 6000 mg; (c) when administered to the patient in need thereof, the dosage form is sufficient to provide an in vivo plasma profile of threonic acid comprising a mean Cavg between about 5 μg / mL to about 20 μg / mL.SELECTED DRAWING: None

Description

[Background technology]

[0001] Magnesium is one of the most abundant minerals in the human body and plays multiple roles in maintaining good health.Examples of magnesium's role in living cells include the homeostasis of other minerals, such as sodium, potassium and calcium, and the formation, transport, storage and utilization of adenosine triphosphate (ATP), the main source of energy in living cells.Other functions of magnesium in the human body include maintaining normal muscle and nerve activity, heart rhythm, bone strength and immune system health.

[0002] It is estimated that the majority of the people in the United States do not consume enough magnesium, and therefore may be magnesium deficient.Magnesium deficiency, including hypomagnesia, refers to insufficient dietary intake of magnesium or magnesium malabsorption.Magnesium deficiency is also associated with many conditions and diseases, including hypertension, atherosclerosis, arrhythmia, diabetes and metabolic syndrome.Magnesium deficiency may also be correlated with neurological disorders, including dementia, Alzheimer's disease and depression.

[0003] In general, magnesium compounds have low bioavailability and are ineffective in increasing magnesium concentration in the central nervous system (CNS). However, magnesium threonate has high bioavailability compared to other magnesium compounds and can significantly increase CNS magnesium concentration by itself. Specifically, magnesium threonate can increase magnesium concentration in neuronal synapses, which is important for proper synaptic and neurological function. Research has shown that magnesium threonate can improve many diseases, disorders, syndromes and conditions. For example, it can improve learning and memory, reduce neuropsychiatric symptoms, reduce neuropathic pain, and inhibit cancer cell proliferation and migration. Summary of the Invention [Means for solving the problem]

[0004] A dosage form comprising magnesium threonate for the treatment of a disease, disorder, syndrome or condition in a patient in need thereof, comprising: (a) at least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the salt form of MgT2; (b) magnesium threonate is present in an amount of about 200-6000 mg; (c) When administered to a patient in need thereof, the dosage form has a mean C of about 5 μg / mL to about 20 μg / mL. avg A dosage form is provided that is sufficient to provide an in vivo plasma profile of threonic acid comprising:

[0005] A dosage form comprising magnesium threonate, (a) at least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the salt form of MgT2; (b) magnesium threonate is present in an amount of about 200 to 6000 mg; and (c) an in vivo plasma profile from said dosage form exhibits a variation index that is less than about 170%.

[0006] A dosage form comprising magnesium threonate, (a) at least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the salt form of MgT2; (b) magnesium threonate is present in an amount of about 200 to 6000 mg; and (c) The release of magnesium threonate from the dosage form lasts for about 0.2 h, as calculated from measurements obtained using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of about 37° C. -1 ~0.6h -1 Also provided is a dosage form that exhibits a first order release constant of

[0007] A dosage form comprising magnesium threonate, (a) at least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the salt form of MgT2; (b) magnesium threonate is present in an amount of about 17.5 mg / kg LBM / dose; and (c) When administered to a patient in a fed state, the dosage form is: (i) a mean AUC over 24 hours of at least about 70 μg h / mL (AUC 0-24 ); (ii) a mean C of less than about 13 μg / mL max Also provided is a dosage form sufficient to provide an in vivo plasma profile of threonic acid comprising:

[0008] Methods for using the dosage forms described herein for the treatment of a disease, disorder, syndrome, or condition are also provided.

[0009] Methods for preparing the dosage forms described herein are also provided.

[0010] These and other aspects of the invention will become apparent upon reference to the following detailed description, and for this purpose, 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.

[0011] The novel features of the invention are particularly set forth 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 and the accompanying drawings (also referred to herein as "Figure" and "Fig."), which illustrate illustrative embodiments, in which the principles of the invention are utilized. [Brief description of the drawings]

[0012] [Figure 1A-1D] 1 shows the threonate dissolution profile of a dosage form containing magnesium threonate. [Fig. 2A-2F]1 shows the plasma concentration profile of a dosage form containing magnesium threonate. [Diagram 3] 1 shows modeled plasma concentration profiles from theoretical repeated dosing of a dosage form containing magnesium threonate. [Figure 4] FIG. 1 illustrates neuropsychological test battery z-scores for patients treated with magnesium threonate dose based on total body weight (TBW) or lean body mass (LBM) dose. [Figure 5A-5C] Illustrated are mood (anxiety and depression z-scores), global cognition (z-score composite of working memory, processing speed and cognitive flexibility) and working memory (backward digit span task) respectively in human subjects orally administered a dosage form containing magnesium threonate. [Figure 6] 1 shows the threonate dissolution profile of a dosage form containing magnesium threonate. [Figure 7] 1 shows the threonate dissolution profile of a dosage form containing magnesium threonate. [Figure 8] 1 shows a dose-response curve for magnesium threonate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] While preferred embodiments of the present invention are shown and described herein, such embodiments It will be apparent to those skilled in the art that the embodiments described herein are provided by way of example only. Those skilled in the art will immediately recognize numerous variations, changes, and substitutions without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be used in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0014] In the following description, certain specific details are given to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present invention may be practiced without these details. In other instances, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, throughout the following specification and claims, the word "comprise" and variations thereof, such as "comprises" and "including", are to be interpreted in an open and inclusive sense, i.e., "including but not limited to". Moreover, the headings provided herein are merely for convenience and do not describe the scope or meaning of the claimed invention.

[0015] Throughout this specification, references to "one embodiment," or "an embodiment," or "some embodiments," or "particular embodiments" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment," or "in an embodiment," or "in some embodiments," or "in a particular embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0016] Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0017] Generally, the term "magnesium threonate" refers to the MgT2 salt form as exemplified by the formula provided below. [ka] Magnesium threonate may also be called magnesium L-threonate, magnesium (2R,3S)-2,3,4-trihydroxybutanoate, L-threonic acid magnesium salt (L-TAMS), MgT, or Magtein.

[0018] In general, the term "threonate" refers to threonate and / or threonate precursors.

[0019] In general, the term "threonate precursor" refers to a precursor molecule that can be readily converted to threonate when the composition is dissolved in an aqueous medium or ingested as a result of ionization or hydrolysis with or without the aid of enzymes. The precursor of the L-threonate may be L-threonate, threonic acid, ester derivative of threonate, or lactonized threonate. Generally, threonate refers to L-threonate. For example, the precursor of the L-threonate is L-threonate, ester derivative of L-threonate, or lactonized L-threonate. In some embodiments, D-threonate or its precursor is used.

[0020] In general, the term "elemental magnesium" when used in connection with the magnesium-counter ion compounds described herein refers to the total amount of magnesium present as free ion and magnesium bound to one or more counter ions. In general, such term is not used to refer to magnesium associated with substances other than the magnesium-counter ion compounds that are components of the magnesium-counter ion composition (e.g., pharmaceutical compositions, dietary supplement compositions, foods supplemented with magnesium-counter ion compounds). Small amounts of magnesium may be naturally present in or associated with such substances. For example, a fruit juice extract or flavoring may contain the amount of magnesium naturally present in the fruit from which it is derived.

[0021] In general, the term "bioavailability" refers to the rate and extent to which an active substance or its active form is absorbed from a formulation (e.g., an oral dosage form) and becomes available at the site of action. See US Code of Federal Regulations, Title 21, Part 320.1 (2001 ed.). For oral dosage forms, bioavailability generally refers to the process by which an active ingredient is released from an oral dosage form (e.g., a tablet), converted to an active form (if the active ingredient is not already in an active form), transported to the site of action, and absorbed, for example, into the systemic circulation. Changes in drug bioavailability due to oral dosage forms can be determined by measuring the total systemic drug concentration over time after administration of different oral dosage forms. Drug bioavailability is defined as the area under the curve (AUC). AUC can be the integral of the systemic drug concentration over time in units of mass-time / volume (e.g., microgram-time / milliliter or μg-time / mL). Alternatively, or in addition, AUC can be the integral of the systemic drug concentration over a defined, measurable length of time. The AUC over the first 12 or 24 hours after administration of an oral dosage form, respectively, is AUC 0-12 or AUC 0-24 It can be called.

[0022] In general, C max The term refers to the peak plasma concentration of a drug.

[0023] In general, T max The term refers to the time to reach peak plasma concentration.

[0024] In general, T 1 / 2 Or the term terminal half-life refers to the time required for the plasma concentration of a drug to be halved after pseudoequilibrium is reached.

[0025] In general, the term "cognition" refers to the process of acquiring, constructing, understanding, processing, and / or using information or knowledge. In general, enhancing cognitive function refers to enhancing any aspect of such a process, such as, for example, learning, performance of intellectual activities, storing, recalling, and / or using information, and / or thinking, remembering, and / or preventing the decline of a subject's cognitive status. Various standardized tests can be used to assess cognition, cognitive function, and / or cognitive status, and can be used to identify subjects who may be benefiting from and / or in need of its maintenance and / or enhancement, and / or to monitor the effectiveness of treatment thereon. Examples of suitable tests include the Mini-Mental Status Exam (Folstein, 1975), components of the PROSPER neuropsychological test battery (Houx, 2002), and / or the like. Family history, age, and / or other factors can also be used to identify subjects who may be benefiting from and / or in need of its maintenance and / or enhancement.

[0026] In general, the "dissolution profile", i.e., the extent of release of magnesium and / or threonate over a desired time period, can be conveniently determined for a given time period by measuring the release under controlled conditions, e.g., using a USP dissolution apparatus. A preferred release profile is one that slows the rate of uptake of threonate and / or magnesium into the bloodstream while providing therapeutically effective levels of threonate and / or magnesium. Following the guidelines of standardized dissolution tests for sustained release profiles, dissolution of the active ingredient is measured at intervals over time. A minimum of three time points is recommended, which generally covers the early, middle and late stages of the dissolution profile. The last measurement should not be earlier than the time point at which at least 80 percent (%) of the active ingredient has been dissolved (Guidance for Industry, "Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro / In Vivo Correlations", Food and Drug Administration, 2002). (Food and Drug Administration, CDER, September 1997, Page 17). Accurate sampling is important, e.g., at 1, 2, and 4 hours and then every 2 hours until 80% of the active ingredient is released (Guidance for Industry, SUPAC-MR: Modified Release Solid Oral Dosage Forms, “Food and Drug Administration, CDER, September 1997, Page 6). The preferred dissolution apparatus is USP Apparatus I (basket) or II (paddle), used at an acceptable rotation speed, e.g., 100 revolutions per minute (rpm for basket and 50-75 rpm for paddle) (Guidance for Industry, “Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In ("Dissolution Testing of Drugs for In Vitro / In Vivo Correlations", Food and Drug Administration, CDER, September 1997, Page 4). Sustained release dosage forms allow for the release of the active ingredient over an extended period of time. On the other hand, a material that dissolves at least 80% in solution within the first 30 to 60 minutes is considered to have an immediate release (IR) profile. ("Dissolution Testing of Drugs for In Vitro / In Vivo Correlations", Food and Drug Administration, CDER, September 1997, Page 4). "Immediate Release Solid Oral Dosage Forms", published August 1997, Section IV-A).

[0027] In general, the term "dose proportionality" as used herein refers to the relationship between the dose of active ingredient and its bioavailability.For example, dose proportionality exists when twice the same composition delivers twice the active ingredient and provides the same bioavailability as one administration of this dosage form.Dose proportionality applies to a wide range of doses as discussed in detail herein.

[0028] In general, the term "effective amount" refers to an amount of an active agent that is sufficient to exert a particular biological state, effect, and / or response with respect to the active agent. The absolute amount of a particular agent that is thus effective may vary depending, for example, on various factors, such as the desired biological endpoint, the agent itself, the subject or its targeting portion, and / or the like. An effective amount of an active agent may be administered in a single dose or in multiple doses. Examples of biological states, effects, or responses that may be produced by an effective amount of an active agent include, for example, maintaining and / or improving a subject's performance in a task that includes or is associated with cognitive function, maintaining and / or improving a subject's performance in a test that measures something related to or associated with cognitive function, maintaining and / or improving (e.g., slowing) the rate of decline in cognitive function, and / or the like. The components may be any of those described herein that have at least an effective amount or at least an effective amount, such as those associated with a particular goal or objective, such as any of those described herein.

[0029] Generally, the term "fasted state" refers to a subject's feeding state in which the patient consumes a standard meal and fasts for about 6 hours (h), 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 6-10 h, 8-12 h, or 6-16 h prior to administration of the dosage form. The patient may fast for about an additional 4 hours following administration.

[0030] In general, the term "fed state" refers to a subject's eating state in which the patient consumes a standard meal, fasts for about 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 6-10 h, 8-12 h, or 6-16 h, and consumes another meal about 30 minutes prior to administration of the dosage form. The patient may fast for about an additional 4 hours after administration.

[0031] In general, the term "peak" refers to the peak plasma concentration (C) of a drug that the drug achieves after it is administered and before the second dose is administered. max ) and minimum plasma concentration (C min Without wishing to be bound by theory, a smaller increase or decrease may indicate a steady state bioavailability of the active agent.

[0032] In general, the term "variability index" refers to avg The increase or decrease as a percentage of (C max -C min ), that is, ((C max -C min ) / C avg ) * 100% (where C avg refers to AUC / time interval).

[0033] In general, the term "modified release" refers to a mechanism of delivery of a drug with a delay after its administration (delayed release dosing) or over an extended period of time (sustained release dosing) or to a specific target in the body (targeted release dosing). Sustained release includes sustained release and controlled release. Sustained release refers to maintaining drug release over an extended period of time, but not at a constant rate, e.g., first order release. Controlled release refers to maintaining drug release at an approximately constant rate, e.g., zero order release, over an extended period of time.

[0034] In general, the term "pharmacokinetics" (PK) refers to the study of the fate of pharmaceuticals from the time they are ingested until they are eliminated from the body. The sequence of events for oral compositions may include absorption through various mucosal surfaces, distribution to various tissues via the bloodstream, biotransformation in the liver and other tissues, action at target sites, and excretion of the drug or metabolites in the urine or bile.

[0035] In general, the terms "physiologically acceptable" or "pharmaceutical acceptable" refer to biologically or pharmacologically compatible for in vivo use in animals, or humans, as approved, for example, by a regulatory agency of the United States or state government, or as listed in the United States Pharmacopeia or other generally recognized pharmacopoeias, in animals, or more specifically, in humans.

[0036] In general, the term "oral dose" or "oral dosage form" refers to any orally administered composition that contains magnesium (Mg) and threonate (T) as active substances. In some cases, the oral dosage form includes a single type of oral dosage form (e.g., tablet, gel, etc.). Each of the single type of oral dosage form may include one or more unit doses, or may include 1-10 unit doses (e.g., 1-10 tablets), 1-5 unit doses, or 1-3 unit doses. The unit doses may be taken in the form of tablets, pills, gels, capsules, soft gelatin capsules, or any other manner disclosed herein or known in the art. In some cases, the oral dosage form includes two or more types of oral dosage forms (e.g., pills and tablets) or two to five types of oral dosage forms. Each of the two or more types of oral dosage forms may include one or more unit doses (e.g., one pill and two tablets, two pills and one tablet, two pills and two tablets, etc.).

[0037] In general, the term "systemic drug concentration" refers to any concentration in blood or plasma, serum, urine, saliva, and / or other fluids. The term refers to the concentration of a drug in a mammalian bodily fluid, such as an easily sampled bodily fluid of the body. The term may also include the concentration of a drug in tissues bathed by systemic fluids, including the skin.

[0038] In general, the term "skewness" refers to the characteristic degree of asymmetry of the plasma concentration profile around the mean plasma concentration value.

[0039] In general, the term "subject" refers 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 individuals or patients to whom the composition is to be administered for experimental, diagnostic, nutritional, and / or therapeutic purposes. The subject or patient may be in normal, good or excellent health, mood, cognition, and / or nutritional status, or in poor health, mood, cognition, and / or nutritional status, including abnormal, poor, damaged, unhealthy, impaired, diseased, and / or undernourished. The subject may be of any age, including elderly.

[0040] As used herein, the term "tablet" refers generally to tablets, caplets, capsules, including soft gelatin capsules, and lozenges.

[0041] As used herein, the term "treat" in all its verb forms includes alleviating or improving at least one symptom of a disorder in a subject, such as pain, Alzheimer's disease, vascular dementia, or Parkinson's disease. The term "treat" can mean alleviating or improving the intensity and / or duration of manifestations of the disorder experienced by a patient in response to a stimulus (e.g., blood pressure, tissue damage, cold temperature, etc.). For example, with respect to dementia, the term "treat" can mean alleviating or improving cognitive impairment (such as memory and / or orientation failure) or global function (activities of daily living, ADL) failure, and / or slowing or reversing the progression of ADL or cognitive deterioration. The term "treat" also refers to halting, delaying (i.e., the period before clinical symptoms of the disease) onset, and / or reducing the risk of onset or worsening of the disease. The term "protect" is used herein to mean preventing, delaying, or treating, as appropriate, the onset or persistence or progression of the disease in a subject. Dementia is associated with CNS disorders, including, but not limited to, neurodegenerative diseases such as Alzheimer's disease (AD), Down's syndrome, and vascular dementia (VaD). The term "treatment", as defined above, includes the act of "treating".

[0042] Dosage forms are provided that contain magnesium (Mg) and threonate (T) that are formulated and / or administered to provide serum or plasma concentrations over a desired period of time that are high enough to be physiologically effective, but not too high at any given time so as not to cause adverse events or reduce the physiological effect.

[0043] The dose-response curve for magnesium threonate is bell-shaped (FIG. 8), with efficacy decreasing as the dosage increases beyond a certain point. The concentration range for magnesium threonate to achieve a therapeutic response is relatively small. This unique property of magnesium threonate indicates that for a given AUC, efficacy can be influenced by the shape of the serum or plasma concentration profile. For dosage forms, sustained release of magnesium threonate can be used to lower and delay peak plasma levels while maintaining physiologically effective blood concentrations. Sustained release formulations have less variability than both immediate release and zero-order controlled release dosage forms (Table 2), resulting in better efficacy (see, e.g., FIG. 5). Furthermore, the delayed time to obtain peak serum or plasma levels and the longer duration of therapeutically effective serum or plasma levels can result in reduced dosing frequency, e.g., to once or twice daily dosing, thereby improving compliance and adherence in subjects. The reduced concentration variability also reduces the active ingredient concentration at its maximum, providing a more consistent and more consistent dose for those undergoing treatment over a period of time. This provides elephants with a more consistent amount of magnesium threonate.

[0044] A dosage form comprising magnesium threonate for the treatment of a disease, disorder, syndrome or condition in a patient in need thereof, comprising: (a) at least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the salt form of MgT2; (b) magnesium threonate is present in an amount of about 200-6000 mg; (c) When administered to a patient in need thereof, the dosage form has a mean C of about 5 μg / mL to about 20 μg / mL. avg A dosage form is provided that is sufficient to provide an in vivo plasma profile of threonic acid comprising:

[0045] A dosage form comprising magnesium threonate, (a) at least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the salt form of MgT2; (b) magnesium threonate is present in an amount of about 200 to 6000 mg; and (c) an in vivo plasma profile from said dosage form exhibits a variation index that is less than about 170%.

[0046] A dosage form comprising magnesium threonate, (a) at least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the salt form of MgT2; (b) magnesium threonate is present in an amount of about 200 to 6000 mg; and (c) The release of magnesium threonate from the dosage form lasts for about 0.2 h, as calculated from measurements obtained using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of about 37° C. -1 ~0.6h -1 Also provided is a dosage form that exhibits a first order release constant of

[0047] A dosage form comprising magnesium threonate, (a) at least a portion of the magnesium (Mg) and threonate (T) of the magnesium threonate is present in the salt form of MgT2; (b) the magnesium threonate is present in an amount of about 200 to 6000 mg; and (c) an in vivo plasma profile from said dosage form exhibits a skewness that is less than about 0.2.

[0048] A dosage form comprising magnesium threonate, (a) at least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the salt form of MgT2; (b) magnesium threonate is present in an amount of about 17.5 mg / kg LBM / dose; and (c) When administered to a fed patient at therapeutic doses, the dosage form: (i) a mean AUC over 24 hours of at least about 70 μg h / mL (AUC 0-24 ); and (ii) a mean C of less than about 13 μg / mLmax Also provided is a dosage form sufficient to provide an in vivo plasma profile of threonic acid comprising:

[0049] In some embodiments, the dosage form is formulated for oral administration. In some embodiments, the dosage form has a mean T of at least about 4.5 hours. max is sufficient to provide an in vivo plasma profile of threonate comprising:

[0050] In some embodiments, the dosage form is liquid, semi-liquid, semi-solid, or solid. In one embodiment, the dosage form is a gel, pill, tablet, capsule, bead, emulsion, granule, paste, pellet, powder, syrup, suspension, slurry, or aerosol.

[0051] In some embodiments, the dosage form comprises at least two or more unit doses, e.g., two tablets are administered simultaneously. When comprising two or more unit doses, each unit dose exhibits substantially the same in vitro dissolution profile in a dissolution medium. Alternatively, when comprising two or more unit doses, each unit dose exhibits a different in vitro dissolution profile in a dissolution medium. In some embodiments, the dosage form comprises three identical tablets, the three identical tablets exhibiting substantially the same in vitro dissolution profile in a dissolution medium. In some embodiments, the dosage form comprises one tablet and one capsule, the tablet and the capsule exhibiting different in vitro dissolution profiles in a dissolution medium. In some embodiments, the dosage form comprises two or more individual unit doses, the unit doses exhibiting substantially the same in vitro dissolution profile in a dissolution medium.

[0052] In some embodiments, the release of magnesium threonate from the dosage form is approximately 0.2 h, as calculated from measurements obtained using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of approximately 37° C. -1 ~0.6h -1In some embodiments, the first order release constant is about 0.25-0.45 as calculated from measurements obtained using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of about 37° C. In some embodiments, the first order release constant is about 0.3 h as calculated from measurements obtained using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of about 37° C. -1 ~0.4h -1 It is.

[0053] In some embodiments, the in vivo plasma profile from the dosage form exhibits a variability index that is less than about 170%. In some embodiments, the in vivo plasma profile from the dosage form exhibits a variability index that is less than about 165%. In some embodiments, the in vivo plasma profile from the dosage form exhibits a variability index that is less than about 160%. In some embodiments, the in vivo plasma profile from the dosage form exhibits a variability index that is less than about 155%.

[0054] In some embodiments, the in vivo plasma profile from the dosage form exhibits a skewness that is less than about 0.2.

[0055] In some embodiments, the first order release constant is about 0.25 h 2 O, calculated from measurements obtained using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of about 37° C. -1 ~0.45h -1 and the in vivo plasma profile from the dosage form exhibits a variation index that is less than about 170%. In some embodiments, the first order release constant is about 0.3 h, calculated from measurements obtained using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of about 37° C. -1 ~0.4h -1 and the in vivo plasma profile from said dosage form exhibits a variation index that is less than about 170%.

[0056] In some embodiments, when administered to a fed patient, the dosage form is sufficient to provide an in vivo plasma profile of threonic acid comprising a mean gain / loss value of less than about 14 μg / mL. In some embodiments, the dosage form comprises a mean gain / loss value (C) of less than about 14 μg / mL, 13 μg / mL, 12 μg / mL, 11 μg / mL, 10 μg / mL, 9 μg / mL, 8 μg / mL, 7 μg / mL, 6 μg / mL, 5 μg / mL or less. max -C min In some embodiments, the increment (C max -C min ) is about 14 μg / mL to about 5 μg / mL, about 12 μg / mL to about 8 μg / mL, about 11 μg / mL to about 9 μg / mL, or about 11 μg / mL to about 10 μg / mL. In some embodiments, the dosage form contains a mean gain or loss of administered magnesium threonate of less than about 10 μg / mL / g. In some embodiments, when administered to a fed patient, the dosage form is sufficient to provide an in vivo plasma profile of threonate comprising a mean gain / loss of less than about 10 μg / mL / g of administered magnesium threonate.

[0057] The model graph shows that theoretical dosing of Formulation B every 12 hours would result in a lower gain / loss value (10.9) than Formulation A (14.2) (Figure 3).

[0058] In some embodiments, the in vitro dissolution profile of the dosage form in the dissolution medium ranges from about 10-50% at about 1 hour. In some embodiments, the in vitro dissolution profile of the dosage form in the dissolution medium ranges from about 10-60% at about 2 hours. In some embodiments, the in vitro dissolution profile of the dosage form in the dissolution medium ranges from about 20-80% at about 4 hours. In some embodiments, the in vitro dissolution profile of the dosage form in the dissolution medium ranges from about 50-90% at about 6 hours. In some embodiments, the in vitro dissolution profile of the dosage form in the dissolution medium ranges from greater than or equal to: (i) about 10-50% at about 1 hour, (ii) about 10-60% at about 2 hours, (iii) about 20-80% at about 4 hours, iv) about 50-90% at about 6 hours, and (v) about 80% at about 8 hours, as measured using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of about 37°C.

[0059] In some embodiments, when administered to a patient in need thereof, the dosage form has a mean C avg In some embodiments, when administered to a patient in need thereof, the dosage form has a mean C of about 5 μg / mL to about 15 μg / mL. avg is sufficient to provide an in vivo plasma profile of threonate comprising:

[0060] In some embodiments, the dosage form has a mean AUC 0-24 In some embodiments, when administered to a fed patient, the dosage form provides a mean AUC of at least about 55 μg h / mL based on a dose of 17.5 mg / kg LBM / dose. 0-24In some embodiments, the dosage form, when administered in vivo, is sufficient to provide an in vivo plasma profile of threonic acid comprising at least about 50 μg·h / mL, 80 μg·h / mL, 90 μg·h / mL, 100 μg·h / mL, 110 μg·h / mL, 120 μg·h / mL, 130 μg·h / mL, 140 μg·h / mL, 150 μg·h / mL, 160 μg·h / mL, 170 μg·h / mL, 180 μg·h / mL, 190 μg·h / mL, 200 μg·h / mL, 300 μg·h / mL, 400 μg·h / mL, 500 μg·h / mL or more of a mean AUC over 24 hours (AUC 0-24 In some embodiments, the threonate is formulated to provide an in vivo plasma profile of threonate comprising AUC 0-24 is about 100 μg·h / mL to about 500 μg·h / mL, about 100 μg·h / mL to about 200 μg·h / mL, or about 103 μg·h / mL to about 120 μg·h / mL. 0-24 and AUC measured under fasting conditions 0-24 % variation between (AUC 0-24 Satiation-AUC 0-24 Fasting) / AUC 0-24 Fasting) is at least 50% greater, 100%, 150% greater, or greater than AUC measured under fed conditions. 0-24 and AUC measured under fasting conditions 0-24 The absolute variation between is at least about 20 μg·h / mL, 25 μg·h / mL, 30 μg·h / mL, 35 μg·h / mL or more.

[0061] In some embodiments, the dosage form has a mean C of less than about 13 μg / mL, based on a dose of 17.5 mg / kg LBM / dose. max In vivo plasma profile of threonate containing In some embodiments, when administered to a fed patient, the dosage form provides a mean C of less than about 13 μg / mL, based on a dose of 17.5 mg / kg LBM / dose. max is sufficient to provide an in vivo plasma profile of threonate comprising:

[0062] In some embodiments, the dosage form has a mean C of less than about 12 μg / mL, 11 μg / mL, 10 μg / mL, 9 μg / mL, 8 μg / mL, 7 μg / mL, 6 μg / mL, or 5 μg / mL. max In some embodiments, the dosage form provides an in vivo plasma profile of threonic acid comprising a mean C of about 17 μg / mL to about 10 μg / mL, about 17 μg / mL to about 15 μg / mL, about 16 μg / mL to about 10 μg / mL, or about 16 μg / mL to about 12 μg / mL. max The present invention provides an in vivo plasma profile of threonic acid, including

[0063] In some embodiments, the dosage form has a mean T of at least about 4.5 hours (h), 5 h, 5.5 h, 6 h, 6.5 h, 7 h, 7.5 h, 8 h, 8.5 h, 9 h, 9.5 h, 10 h or more. max The present invention provides an in vivo plasma profile of threonic acid, including

[0064] In some embodiments, the dosage form is sufficient to provide at least about 15-30 mg / kg lean body mass / dose (30-60 mg / kg LBM / day) of magnesium threonate when given every 12 hours in a patient in need of treatment for a disease, disorder, syndrome, or condition. In some embodiments, the dosage form is sufficient to provide at least about 15 mg / kg lean body mass / dose of magnesium threonate when given every 12 hours in a patient in need of treatment for a disease, disorder, syndrome, or condition. In some embodiments, the dosage form is sufficient to provide at least about 15 mg / kg lean body mass / dose of magnesium threonate when given every 24 hours in a patient in need of treatment for a disease, disorder, syndrome, or condition. In some embodiments, the dosage form is sufficient to provide at least about 10-30 mg / kg lean body mass / dose of magnesium threonate when given every 24 hours in a patient in need of treatment for a disease, disorder, syndrome, and / or condition. In some embodiments, the dosage form is sufficient to provide at least about 30 mg / kg lean body weight / day of magnesium threonate, hi some embodiments, the dosage form is sufficient to provide about 20-60 mg / kg lean body weight / day of magnesium threonate.

[0065] In some embodiments, the dosage form is sufficient to provide magnesium threonate in an amount of about 35 mg / kg LBM / day to about 50 mg / kg LBM / day. In some embodiments, the dosage form is sufficient to provide magnesium threonate in an amount of at least about 35 mg / kg LBM / day. In some embodiments, the dosage form is sufficient to provide magnesium threonate in an amount of up to about 50 mg / kg LBM / day. In some embodiments, the dosage form comprises about 35 mg / kg LBM / day to about 36 mg / kg LBM / day, about 35 mg / kg LBM / day to about 37 mg / kg LBM / day, about 35 mg / kg LBM / day to about 38 mg / kg LBM / day, about 35 mg / kg LBM / day to about 39 mg / kg LBM / day, about 35 mg / kg LBM / day to about 40 mg / kg LBM / day, about 35 mg / kg LBM / day to about 42 mg / kg LBM / day, about 35 mg / kg LBM / day to about 44 mg / kg LBM / day, about 35 mg / kg LBM / day to about 46 mg / kg LBM / day, about 35 mg / kg LBM / day to about 48 mg / kg LBM / day, about 35 mg / kg LBM / day to about 50 mg / kg LBM / day, about 36 mg / kg LBM / day to about 37 mg / kg LBM / day LBM / day, approximately 36mg / kg LBM / day ~ approximately 38mg / kg LBM / day, approximately 36mg / kg LBM / day ~ approximately 39mg / kg LBM / day, approximately 36mg / kg LBM / day ~ approximately 40mg / kg LBM / day, approximately 36mg / kg LBM / day ~ approximately 42mg / kg LBM / day, approximately 36mg / kg LBM / day ~ approximately 44mg / kg LBM / day, approx. 36mg / kg LBM / day ~ approx. 46mg / kg LBM / day, approx. 36mg / kg LBM / day ~ approx. 48mg / kg LBM / day, approx. 36mg / kg LBM / day to about 50mg / kg LBM / day, about 37mg / kg LBM / day to about 38mg / kg LBM / day, about 37mg / kg LBM / day to about 39mg / kg LBM / day, about 37mg / kg LBM / day to about 40mg / kg LBM / day, about 37mg / kg LBM / day to about 42mg / kg LBM / day, about 37mg / kg LBM / day to about 44mg / kg LBM / day, about 37mg / kg LBM / day to about 46mg / kg LBM / day, about 37mg / kg LBM / day to about 48mg / kg LBM / day, about 37mg / kg LBM / day to about 50mg / kg LBM / day, about 38mg / kg LBM / day to about 39mg / kg LBM / day, about 38mg / kg LBM / day to about 40mg / kg LBM / day, about 38mg / kg LBM / day to about 42mg / kg LBM / day, about 38mg / kg LBM / day to about 44mg / kg LBM / day, about 38mg / kg LBM / day to about 46mg / kg LBM / day, about 38mg / kg LBM / day to about 48mg / kg LBM / day, about 38mg / kg LBM / day to about 50mg / kg LBM / day, about 39mg / kg LBM / day to about 40mg / kg LBM / day, about 39mg / kg LBM / day to about 42mg / kg LBM / day, about 39mg / kg LBM / day to about 44mg / kg LBM / day, about 39mg / kg LBM / day to about 46mg / kg LBM / day, about 39mg / kg LBM / day to about 48mg / kg LBM / day, about 39mg / kg LBM / day to about 50mg / kg LBM / day, about 40mg / kg LBM / day to about 42mg / kg LBM / day, about 40mg / kg LBM / day to about 44mg / kg LBM / day, about 40mg / kg LBM / day to about 46mg / kg LBM / day, about 40mg / kg LBM / day to about 48mg / kg LBM / day, about 40mg / kg LBM / day to about 50mg / kg LBM / day, about 42mg / kg LBM / day to about 44mg / kg LBM / day, about 42mg / kg LBM / day to about 46mg / kg LBM / day, about 42mg / kg LBM / day to about 48mg / kg LBM / day, about 42mg / kg LBM / day to about 50mg / kg LBM / day, about 44mg / kg LBM / day to about 46mg / kg LBM / day, about 44mg / kg LBM / day to about 48mg / kg LBM / day, about 44mg / kg LBM / day to about 48mg / kg LBM / dayThe dosage form is sufficient to provide magnesium threonate in an amount of about 35 mg / kg LBM / day, about 36 mg / kg LBM / day, about 37 mg / kg LBM / day, about 38 mg / kg LBM / day, about 39 mg / kg LBM / day, about 40 mg / kg LBM / day, about 42 mg / kg LBM / day, about 44 mg / kg LBM / day, about 46 mg / kg LBM / day, about 48 mg / kg LBM / day, or about 50 mg / kg LBM / day.

[0066] In some embodiments, the dosage form is sufficient to provide magnesium threonate in an amount of at least about 24 mg / kg TBW / day, 25 mg / kg TBW / day, 26 mg / kg TBW / day, 27 mg / kg TBW / day, 28 mg / kg TBW / day, 29 mg / kg TBW / day, 30 mg / kg TBW / day, 31 mg / kg TBW / day, 32 mg / kg TBW / day, 33 mg / kg TBW / day, 34 mg / kg TBW / day, 35 mg / kg TBW / day or more. In some embodiments, the dosage form is sufficient to provide magnesium threonate in an amount of at most about 35 mg / kg TBW / day, 34 mg / kg TBW / day, 33 mg / kg TBW / day, 32 mg / kg TBW / day, 21 mg / kg TBW / day, 30 mg / kg TBW / day, 29 mg / kg TBW / day, 28 mg / kg TBW / day, 27 mg / kg TBW / day, 26 mg / kg TBW / day, 25 mg / kg TBW / day, 24 mg / kg TBW / day or less.

[0067] In some embodiments, MgT2 is present in an amount equivalent to at least about 20 milligrams (mg) of magnesium (Mg) by weight. g) is present in an amount of greater than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or more by weight. In some embodiments, magnesium (Mg) is present in an amount of greater than about 1%, 5% or greater than about 7% by weight. In some embodiments, the average tablet size for round tablets is about 10 mg to 150 mg of elemental Mg, and for capsule-shaped tablets is about 20 mg to 200 mg of elemental Mg.

[0068] In some embodiments, the molar ratio between threonate (T) and magnesium (Mg) is greater than or equal to about 0.1-2.

[0069] In some embodiments, the dosage form contains magnesium threonate in an amount of at least about 200 mg. In some embodiments, the dosage form contains magnesium threonate in an amount of up to about 6,000 mg. In some embodiments, the dosage form contains magnesium threonate in an amount of about 200 mg to about 6,000 mg. In some embodiments, magnesium threonate is present in an amount of about 200 to 4000 mg. In some embodiments, the dosage form contains from about 200 mg to about 300 mg, from about 200 mg to about 400 mg, from about 200 mg to about 500 mg, from about 200 mg to about 1,000 mg, from about 200 mg to about 1,500 mg, from about 200 mg to about 2,000 mg, from about 200 mg to about 2,500 mg, from about 200 mg to about 3,000 mg, from about 200 mg to about 4,000 mg, from about 200 mg to about 5,000 mg, from about 200 mg to about 6,000 mg, from about 300 mg to about 400 mg, from about 300 mg to about 500 mg, from about 300 mg to about 600 mg, from about 300 mg to about 700 mg, from about 300 mg to about 800 mg, from about 300 mg to about 900 mg, from about 300 mg to about 1000 mg, from about 300 mg to about 1500 mg, from about 300 mg to about 1600 mg, from about 300 mg to about 1700 mg, from about 300 mg to about 1800 mg, from about 300 mg to about 2000 mg, from about 300 mg to about 2500 mg, from about 300 mg to about 2600 mg, from about 300 mg to about 2700 mg, from about 300 mg to about 3500 mg, from about 350 mg to about 2800 mg, from about 350 mg to about 3600 mg, from about 350 mg to about 2900 mg, from about 400 mg to about 400 mg, from about 400 mg to about 00mg to about 500mg, about 300mg to about 1,000mg, about 300mg to about 1,500mg, about 300mg to about 2,000mg, about 300mg to about 2,500mg, about 300mg to about 3,000mg, about 300mg to about 4, 000mg, about 300mg to about 5,000mg, about 300mg to about 6,000mg, about 400mg to about 500mg, about 400mg to about 1,000mg, about 400mg to about 1,500mg, about 400mg to about 2,000mg, about 4 00mg~about 2,500mg, about 400mg~about 3,000mg, about 400mg~about 4,000mg, about 400mg~about 5,000mg, about 400mg~about 6,000mg, about 500mg~about 1,000mg, about 500mg~ Approximately 1,500mg, approximately 500mg to approximately 2,000mg, approximately 500mg to approximately 2,500mg, approximately 500mg to approximately 3,000mg, approximately 500mg to approximately 4,000mg, approximately 500mg to approximately 5,000mg, approximately 500mg to approximately 6,000 mg, about 1,000mg to about 1,500mg, about 1,000mg to about 2,000mg, about 1,000mg to about 2,500mg, about 1,000mg to about 3,000mg, about 1,000mg to about 4,000mg, about 1,000mg Approximately 5,000mg, approximately 1,000mg to approximately 6,000mg, approximately 1,500mg to approximately 2,000mg, approximately 1,500mg to approximately 2,500mg, approximately 1,500mg to approximately 3,000mg, approximately 1,500mg to approximately 4,000mg, approximately 1,500mg to about 5,000mg, about 1,500mg to about 6,000mg, about 2,000mg to about 2,500mg, about 2,000mg to about 3,000mg, about 2,000mg to about 4,000mg, about 2,000mg to about 5,000mg, about 2,000mg to about 6,000mg, about 2,500mg to about 3,000mg, about 2,500mg to about 4,000mg, about The dosage form contains magnesium threonate in an amount of about 2,500 mg to about 5,000 mg, about 2,500 mg to about 6,000 mg, about 3,000 mg to about 4,000 mg, about 3,000 mg to about 5,000 mg, about 3,000 mg to about 6,000 mg, about 4,000 mg to about 5,000 mg, about 4,000 mg to about 6,000 mg, or about 5,000 mg to about 6,000 mg. In some embodiments, the dosage form contains magnesium threonate in an amount of about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 1,000 mg, about 1,500 mg, about 2,000 mg, about 2,500 mg, about 3,000 mg, about 4,000 mg, about 5,000 mg, or about 6,000 mg.

[0070] In some embodiments, magnesium threonate is present in the dosage form in an amount of less than about 77.5% by weight. In some embodiments, magnesium threonate is present in the dosage form in an amount of less than about 77% by weight. In some embodiments, magnesium threonate is present in an amount of about 40 to about 77% wt / wt. In some embodiments, magnesium threonate is present in an amount of about 45 to about 70% wt / wt. In some embodiments, magnesium threonate is present in an amount of about 70%. In some embodiments, magnesium threonate is present in an amount of about 53%.

[0071] In some embodiments, the dosage form further comprises carnauba wax as a binder. In some embodiments, the carnauba wax is present in an amount of about 10 to about 30% wt / wt. In some embodiments, the carnauba wax is present in an amount of about 28% wt / wt. In some embodiments, the carnauba wax is present in an amount of about 10% wt / wt.

[0072] In some embodiments, the dosage form further comprises a lubricant. Lubricants include, for example, calcium stearate or magnesium stearate. In some embodiments, the dosage form further comprises magnesium stearate as a lubricant. In some embodiments, the magnesium stearate is present in an amount of about 1 to about 3% wt / wt. In some embodiments, the magnesium stearate is present in an amount of about 1 to about 2% wt / wt. In some embodiments, the magnesium stearate is present in an amount of about 1.4% wt / wt. In some embodiments, the magnesium stearate is present in an amount of about 2% wt / wt.

[0073] In some embodiments, the dosage form further comprises carnauba wax and magnesium stearate. In some embodiments, the weight ratio of carnauba wax to magnesium stearate is greater than about 12. In some embodiments, the weight ratio of carnauba wax to magnesium stearate is at least about 13. The weight ratio of carnauba wax to magnesium stearate is at least about 13, 13.5, 14, 14.5, 15, 16, 17, 18, 19, 20, 30, 40, 50 or more. In some embodiments, the weight ratio of carnauba wax to magnesium stearate is about 20. In some embodiments, the carnauba wax and magnesium stearate, in combination, are present in the dosage form in an amount of at least about 22.5% by weight.

[0074] In some embodiments, the weight ratio of carnauba wax to magnesium stearate is less than about 8. In some embodiments, the weight ratio of carnauba wax to magnesium stearate is about 4-8. In some embodiments, the weight ratio of carnauba wax to magnesium stearate is about 4-6. In some embodiments, the weight ratio of carnauba wax to magnesium stearate is about 5.

[0075] In some embodiments, magnesium threonate is present in an amount of less than about 77% by weight, and the combination of carnauba wax and magnesium stearate is present in an amount of at least about 23% by weight. In some embodiments, magnesium threonate is present in an amount of about 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 60%, 50%, 40%, 30%, 20%, 10% by weight or less. Alternatively or in addition, the combination of carnauba wax and magnesium stearate is present in an amount of at least 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 40%, 50%, 60%, 70%, 90%, 90% by weight or more.

[0076] In some embodiments, magnesium threonate is present in an amount of less than about 77% by weight and the combination of carnauba wax and magnesium stearate is present in an amount of less than about 15% by weight. In some embodiments, magnesium threonate is present in an amount of less than about 60% by weight and the combination of carnauba wax and magnesium stearate is present in an amount of less than about 15% by weight. In some embodiments, magnesium threonate is present in an amount of less than about 40% to 60% by weight. In some embodiments, magnesium threonate is present in an amount of about 50%-55% by weight and the combination of carnauba wax and magnesium stearate is present in an amount of about 10%-15% by weight. In some embodiments, magnesium threonate is present in an amount of about 53% by weight and the combination of carnauba wax and magnesium stearate is present in an amount of about 12% by weight.

[0077] In some embodiments, the dosage form comprises an additional substance.

[0078] In some embodiments, the additional substance is a pharma- ceutically acceptable carrier, hi some embodiments, the pharma-ceutically acceptable carrier is selected from the group consisting of micelles, liposomes, microspheres, nanofibers, and any combination thereof.

[0079] In some embodiments, the additional material is a pharma- ceutically acceptable excipient. The compositions described herein include one or any combination of excipients, such as, but not limited to, diluents, binders, disintegrants, glidants, lubricants, colorants, flavorings, solvents, film-forming polymers, plasticizers, opacifiers, anti-adhesives, and abrasives. In some embodiments, the pharma-ceutically acceptable excipient is selected from the group consisting of binders, bulking agents, lubricants, solubilizers, and any combination thereof. In some embodiments, the pharma-ceutically acceptable excipient is selected from the group consisting of lactose, microcrystalline cellulose, silicon dioxide, titanium dioxide, stearic acid, starch, sodium starch glycolate, povidone, pregelatinized starch, croscarmellose, ethylcellulose, dicalcium phosphate, talc, sucrose, calcium stearate, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, hydrogenated vegetable oil, beeswax, and any combination thereof.

[0080] In some embodiments, the compositions described herein are formulated using any of the following excipients or a combination thereof:

[0081] [Table 1]

[0082] In some embodiments, the magnesium compositions described herein include carriers, such as solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. The use of such media and agents for pharma- ceutical active substances is well known in the art. Acceptable salts may also be used in the compositions, such as inorganic salts, such as hydrochloride, hydrobromide, phosphate, or sulfate, and salts of organic acids, such as acetate, proprionate, malonate, or benzoate. In some embodiments, the compositions also contain liquids, such as water, saline, glycerol, and ethanol, as well as substances such as wetting agents, emulsifying agents, or pH buffering agents. Liposomes, such as those described in U.S. Pat. No. 5,422,120, PCT Publication No. WO 95 / 13796 or WO 91 / 14445, or European Patent No. 524,968 B1, may also be used as carriers.

[0083] In some embodiments, additional materials are added to magnesium threonate as compressibility enhancing agents. Such additional materials include silicon dioxide, non-silicon metal oxides, starch, starch derivatives, surfactants, polyalkylene oxides, cellulose A ethers, cellulose esters, mixtures thereof, and the like. In the aqueous slurry (and its Specific additional materials that may be included in the resulting agglomerated crystalline cellulose excipient are aluminum oxide, stearic acid, kaolin, polydimethylsiloxane, silica gel, titanium dioxide, diatomaceous earth, pregelatinized starch, corn starch, high amylose corn starch, high amylopectin corn starch, sodium starch glycolate, hydroxylated starch, modified potato starch, mixtures thereof, etc. These additives may be included in any desired amount that would be apparent to one of ordinary skill in the art.

[0084] In addition to one or more active ingredients, additional additives known to those skilled in the art may be added to the novel excipient before preparation of the final product.For example, any generally acceptable soluble or insoluble inactive filler (diluent) material may be included in the final product (e.g., solid dosage form) as needed.In some embodiments, such inactive fillers include monosaccharides, disaccharides, polyhydric alcohols, inorganic phosphates, sulfates or carbonates, and / or mixtures thereof.Examples of suitable inactive fillers include sucrose, dextrose, lactose, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, calcium carbonate, crystalline cellulose, mixtures thereof, etc.

[0085] In some embodiments, the composition includes an excipient that is a swellable material, such as a hydrogel, in an amount that can swell and expand. Examples of swellable materials include hydrophilic polymers that are lightly crosslinked, such crosslinks being formed by covalent or ionic bonds, and interact with water and aqueous biological fluids to swell or expand to some degree of equilibrium. Swellable materials, such as hydrogels, exhibit the ability to swell in water, retain a significant proportion of water within their structure, and when crosslinked, they do not dissolve in water. Swellable polymers can swell or expand to a very high degree, exhibiting a 2-50 fold increase in volume. Specific examples of hydrophilic polymeric materials include poly(hydroxyalkyl methacrylates), poly(N-vinyl-2-pyrrolidone), anionic and cationic hydrogels, polyelectrolyte complexes, poly(vinyl alcohol) with low acetate residues and crosslinked with glyoxal, formaldehyde or glutaraldehyde, methylcellulose crosslinked with dialdehydes, mixtures of crosslinked agar and carboxymethylcellulose, water insoluble water swellable copolymers made by forming a dispersion of finely divided copolymers of maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene crosslinked with 1 mole of maleic anhydride in 0.001 to about 0.5 moles of polyunsaturated crosslinker / copolymer, water swellable polymers of N-vinyl lactams, crosslinked polyethylene oxide, and the like. Other examples of swellable materials include hydrogels exhibiting 0.05-60% crosslinking, hydrophilic hydrogels known as Carbopol™ acid carboxy polymers, Cyanamer™ polyacrylamides, crosslinked water-swellable indene-maleic anhydride polymers, Good-rite™ polyacrylic acid, polyethylene oxide, starch graft copolymers, Aqua-Keeps™ acrylate polymers, diester crosslinked polyglucans, etc. Methods for testing swellable materials for polymer water uptake pressure and hydrogel-water interfacial interactions are described in U.S. Patent No. 4,327,725, issued May 4, 1982, and entitled "Osmotic device with hydrogel driving member."

[0086] In some embodiments, the dosage forms described herein also contain effective amounts of colorants (e.g., titanium dioxide, FD&C. and D.&C. dyes; see Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 5, pp. 857-884, which is hereby incorporated by reference), stabilizers, binders, odor control agents, and preservatives.

[0087] In some embodiments, the additional substance is a nutritionally active substance. In some embodiments, the nutritionally active substance is a calcium-containing substance, an herb, a spice, or the like. In some embodiments, the additional substance is selected from the group consisting of vitamin A, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, niacin, folic acid, biotin, minerals, and any combination thereof. In some embodiments, the additional substance is a threonate precursor.

[0088] An example of an immediate release tablet (Formulation A) is shown in Example 1. Formulation A tablet contains magnesium L-threonate (450 mg) as magnesium composition, carnauba wax as binder, magnesium stearate as lubricant, and coating containing talc as inert powder and hardened vegetable oil. The weight ratio of carnauba wax to magnesium stearate is 12.

[0089] An example of a sustained release tablet (Formulation B) is shown in Example 2. Formulation B tablet contains magnesium L-threonate (500 mg) as magnesium composition, carnauba wax as binder, magnesium stearate as lubricant, and coating containing talc as inert powder and hardened vegetable oil. The weight ratio of carnauba wax to magnesium stearate is 20. The in vitro dissolution profiles of Formulation B at pH 1.1 (denoted as 114), 4.5 (denoted as 124) and 6.8 (denoted as 144) are shown in Figures 1A, 1B and 1C. For Formulation B, the ranges of release profiles of threonate that may be substantially similar to the release profile of magnesium are: (i) about 10-50% in about 1 hour, (ii) about 10-60% in about 2 hours, (iii) about 20-80% in about 4 hours, (iv) about 50-90% in about 6 hours, and (v) greater than or equal to about 95% in about 8 hours, when measured using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of about 37° C. in pH 1.1, 4.5, and 6.8.

[0090] Another example of controlled release tablet (Formulation C) is shown in Example 3. Formulation C tablet contains magnesium L-threonate (450mg or 500mg) as magnesium composition, povidone K-90 as binder, microcrystalline cellulose as glidant, colloidal silicon dioxide as filler, carbopol and carboxymethylcellulose as swelling materials, Starcap starch as inert powder, magnesium stearate lubricant and talc. The in vitro dissolution profile of Formulation C at pH 1.1 (denoted as 116) and 4.5 (denoted as 126) is shown in Figure 1A, 1B and 1D. For Formulation C, the ranges of release profiles of threonate that may be substantially similar to the release profile of magnesium, when measured using a USP Type II (paddle) dissolution system at 75 rpm at pH 1.1 and 4.5, at a temperature of about 37° C., were: (i) about 10-30% in about 1 hour; (ii) about 20-50% in about 2 hours; (iii) about 40-60% in about 4 hours; (iv) greater than or equal to about 70% in about 8 hours; and (v) greater than or equal to about 80% in about 12 hours.

[0091] Another example of a dosage form is Example 7. Formulation D tablets contain an intragranular portion and an extragranular portion. The in vitro dissolution profile of Formula D is shown in Figure 6.

[0092] Examples of in vivo plasma concentration profiles of dosage forms containing magnesium threonate (Formulation A, Formulation B, and Formulation C) are shown in Example 4. In the experiment, human subjects were given three tablets of either Formulation A, Formulation B, or Formulation C, totaling about 1350-1500 mg of magnesium L-threonate. Some of the subjects fasted for at least 10 hours before oral administration of the tablets (fasted state). Some of the subjects consumed a high-fat, high-calorie breakfast within 30 minutes before oral administration of the tablets ("fed state"). Blood samples were collected at several time intervals before administration (baseline) and up to 24 hours after administration. The resulting in vivo plasma concentration profiles are shown in Figures 2A-2F. In the fasted state, oral administration of Formulation C resulted in the greatest mean AUC 0-24 In the fed state, oral administration of Formula C showed a maximum increase in saturation compared with Formula B (103.3 μg h / mL) and Formula A (98.2 μg h / mL). The average AUC of 0-24 For all three formulations (Formulation A, Formulation B, and Formulation C), the mean AUC 0-24 In the fed state, the administration of Formula B increased the mean C max (16.1 μg h / mL), the lowest mean T max was maximized (5.3 h) (Table 2). In the fed state, the in vivo plasma concentration profile of Formulation B had a lower skewness value than that of Formulation A (FIG. 2F). Without wishing to be bound by theory, the lower skewness of the in vivo plasma concentration profile of Formulation B may indicate a slower release of the active ingredient (magnesium L-threonate) into the circulation compared to that of Formulation A.

[0093] Also provided is a method of treating a disease, disorder, syndrome or condition in a patient in need of such treatment comprising orally administering a dosage form described herein.

[0094] In some embodiments, the dosage form containing magnesium threonate is administered twice a day. In some embodiments, the dosage form is administered more than twice a day. The dosage form is administered three or more times a day. In some embodiments, the dosage form is administered at intervals of 12 hours.

[0095] In some embodiments, the daily administration of the dosage form is repeated for at least about 5 days (d). In some embodiments, the dosage form is administered for at least about 15 days. The daily administration of the dosage form is repeated for at least about 5d, 6d, 7d, 8d, 9d, 10d, 11d, 12d, 13d, 14d, 15d, 16d, 17d, 18d, 19d, 20d, 21d, 22d, 23d, 24d, 25d or more. In some embodiments, the administration of the dosage form is repeated once a week, twice a week, three times a month, four times a month, five times a month, six times a month, seven times a month or more. In some embodiments, the administration of the dosage form is repeated once a month, twice a month, three times a month, four times a month, five times a month, six times a month, seven times a month or more. In some embodiments, administration of the dosage form (e.g., daily) is repeated for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months or longer. In some embodiments, administration of the dosage form is repeated continuously for the duration of a person's life.

[0096] In some embodiments, the dosage form is administered twice daily with food. In some embodiments, the dosage form is administered to the patient in a fed state. In some embodiments, the method further comprises fasting the patient for at least about 4 hours after orally administering the dosage form. In some embodiments, the dosage form is administered at 12 hour intervals with food. In some embodiments, the patient consumes a meal from about 0.5 h to about 4 h prior to administration of the dosage form. In some embodiments, the patient consumes a meal at least about 0.5 h prior to administration of the dosage form. In some embodiments, the patient consumes a meal at most about 4 hours prior to administration of the dosage form. In some embodiments, the patient is administered the dosage form for about 0.5 h to about 1 h, about 0.5 h to about 1.5 h, about 0.5 h to about 2 h, about 0.5 h to about 2.5 h, about 0.5 h to about 3 h, about 0.5 h to about 3.5 h, about 0.5 h to about 4 h, about 1 h to about 1.5 h, about 1 h to about 2 h, about 1 h to about 2.5 h, about 1 h to about 3 h, about 1 h to about 3.5 h, about 1 h to about 4 h, about 1.5 h h to about 2 h, about 1.5 h to about 2.5 h, about 1.5 h to about 3 h, about 1.5 h to about 3.5 h, about 1.5 h to about 4 h, about 2 h to about 2.5 h, about 2 h to about 3 h, about 2 h to about 3.5 h, about 2 h to about 4 h, about 2.5 h to about 3 h, about 2.5 h to about 3.5 h, about 2.5 h to about 4 h, about 3 h to about 3.5 h, about 3 h to about 4 h, or about 3.5 h to about 4 h. In some embodiments, the patient consumes a meal about 0.5 h, about 1 h, about 1.5 h, about 2 h, about 2.5 h, about 3 h, about 3.5 h, or about 4 h before administration of the dosage form.

[0097] In some embodiments, the patient is suffering from a cardiovascular disease, a neurodegenerative disorder, a sleep disorder, a neurological disorder. The patient is suffering from a disease, disorder, syndrome or condition selected from: neurological injury, developmental disorder / autism spectrum disorder, autoimmune disease, genetic disorder, rheumatic disease, inflammatory disease and physical trauma.

[0098] In some embodiments, the patient suffers from mild cognitive impairment, short-term memory loss, long-term memory loss, Alzheimer's disease, Parkinson's disease, Huntington's disease, autism, schizophrenia, cognitive decline, depression, dementia, attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetes, cardiovascular disease, high blood pressure, migraine, glaucoma, mood disorder, stress, anxiety, depression, sleep disorder, psychosis, metabolic disorder, fatigue, cancer, HIV, hepatitis, spinal cord injury, post-operative recovery, post-traumatic stress disorder, arthritis, neuropathic pain, inflammation, tremors, and fibromyalgia. In some embodiments, the patient suffers from cognitive decline as a secondary effect of disease or medical treatment (HIV disease, cancer, chemotherapy). Magnesium supply may also be useful in maintaining, promoting, and / or improving conditions that may cause loss of body magnesium, including, but not limited to, alcoholism, anorexia, hyper-eating, metabolic syndrome, and nutritional deficiencies.

[0099] In some embodiments, the patient is an adult.

[0100] In some embodiments, the method further comprises determining a physiological concentration of threonic acid in the patient before orally administering the dosage form comprising magnesium threonate. In some embodiments, the method further comprises determining at least one additional physiological concentration of threonic acid in the patient after orally administering the dosage form. In some embodiments, the physiological concentration is a serum concentration, a plasma concentration, a urine concentration, or a cerebrospinal fluid concentration. In some embodiments, the at least one additional physiological concentration of threonate and / or magnesium is measured at about 0.5 h, about 1 h, about 1.5 h, about 2 h, about 2.5 h, about 3 h, about 3.5 h, about 4 h, about 4.5 h, about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, about 10 h, about 11 h, about 12 h, about 13 h, about 14 h, about 15 h, about 16 h, about 17 h, about 18 h, about 19 h, about 20 h, about 21 h, about 22 h, and / or about 23 h after administration.

[0101] Dosage Form B disclosed herein exhibits superior physiological effects when administered in vivo when compared with an immediate release dose of magnesium threonate (Dosage Form A). Such improved physiological effects include, but are not limited to, improved mood and cognitive function, such as working memory, processing speed and cognitive flexibility (see FIG. 5).

[0102] Examples of the effect of drug administration on subjects' TBW and LBM are shown in FIG. 4. In two experiments, male and female human subjects were given a dosage form containing magnesium L-threonate daily for 9-12 weeks. In the first experiment, the dosage of the dosage form was set to correspond to approximately 1.5 g of magnesium L-threonate / day (1.5 g / day) for subjects with TBW of 50-70 kg, and approximately 2 g of magnesium L-threonate / day (2 g / day) for subjects with TBW of 70-100 kg. Male and female subjects aged 50-70 years were administered magnesium L-threonate for 12 weeks. After administration of magnesium L-threonate, efficacy in improving global cognition was determined by changes in performance on a neuropsychological test battery (NTB) consisting of four validated cognitive tests including executive function, working memory, attention, and episodic memory. The NTB score can be expressed as a composite score of the combination of the clinical trial population's standardized scores (z-scores) from the individual cognitive tests. In the second study, male and female patients with schizophrenia aged 18-55 years were given 2 g magnesium L-threonate per day (2g / day). After 9 weeks of magnesium L-threonate administration, efficacy in improving overall cognition was determined by change in performance on the MATRICS Consensus Cognitive Battery (MCCB). The MCCB can also be expressed as a z-score. To assess the overall effect of magnesium L-threonate in the two trials, the z-score from baseline was The data from the two studies were combined using the change. Subjects were divided into high and low dose groups based on the median dose / day by TBW and LBM for all subjects in both studies. The median dose / day by TBW was approximately 24 mg / kg TBW / day, and the median dose / day by LBM was approximately 35 mg / kg LBM / day. When subjects scores were categorized by high and low TBW doses, subjects receiving high doses of drug (>24 mg / kg TBW / day) did not perform better than subjects receiving low doses of drug (<24 mg / kg TBW / day) (Figure 4, plot 410). Also, when subjects were categorized by high and low LBM doses, subjects receiving high doses of drug (>35 mg / kg LBM / day) had significantly greater improvement in overall cognition than subjects receiving low doses of drug (<35 mg / kg LBM / day) (Figure 4B, plot 420). Without wishing to be bound by theory, an estimated dose of magnesium threonate of about 35 mg / kg LBM / day for one or more days may be the minimum therapeutic dose for improving cognitive performance.

[0103] An example of the difference in efficacy between different dosage forms is shown in Figure 5. As shown in Figure 5A, subjects treated with a sustained release dosage form (Formulation B) had smaller variability indexes and significantly better mood z-scores (higher mood scores indicate better moods) than those treated with either an immediate release dosage form (Formulation A) or a placebo. Furthermore, as shown in Figures 5B and 5C, only subjects treated with a sustained release dosage form (Formulation B) had significantly higher composite z-scores and Backspan z-scores than those treated with a placebo. Without wishing to be bound by theory, a dosage form with a certain variability index may effectively improve cognitive performance.

[0104] Methods of making dosage forms comprising magnesium threonate are also provided. In some embodiments, the methods of making the dosage form include forming a mixture comprising magnesium threonate and an additional agent. In some embodiments, the methods of making the dosage form further include formulating the mixture to form the dosage form. In some embodiments, the dosage form comprises magnesium threonate in an amount of about 400-2000 mg.

[0105] Tablets are made by methods known in the art, and in some embodiments further comprise suitable binders, fillers, lubricants, diluents, disintegrants (solubilizers), colorants, flavorings, flow inducers, melting agents, many variations of which are known in the art. In some embodiments, the dosage form has a film coating to protect the components of the magnesium-counter ion supply 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, croscarmellose, and ethylcellulose. In some embodiments, the dosage form comprises a plurality of beads encapsulated in a capsule. Such formulations may be used as sustained release formulations. Other forms of tablets may also be formulated in a sustained release manner. Methods for making sustained release tablets, including controlled release and sustained release, are known in the art, see, for example, US Patent Application Publication Nos. 2006 / 051416 and 2007 / 0065512, or other references disclosed herein.

[0106] In some embodiments, the dosage form is made by mixing powders comprising magnesium (Mg) and threonate (T), both of which may be in salt form, together with a sufficient amount of polymer to create particles comprising magnesium (Mg), threonate (T) and the polymer, the particles being of a size sufficient to be retained by a 12 mesh sieve. In some embodiments, the method includes filtering the particles using a 12 mesh sieve to remove unbound threonate; drying the particles; adding an acceptable amount of lubricant to the particles; compressing the particles into one or more pills having an overall size of about 100 mg to about 2000 mg; and adding one or more of polyvinylpyrrolidone, polyvinyl acetate, polyvinyl ether ... The method further comprises coating one or more pills with a polymer coating comprising propylene glycol and propylene glycol. In some embodiments, the pills are made with an elemental magnesium content of about 10 mg to about 200 mg.

[0107] In some embodiments, the dosage form comprises a plurality of beads, each bead comprising a core having a diameter of about 1 micrometer (μm) to about 1000 μm, the core comprising an active ingredient comprising magnesium or a salt thereof in the range of about 15 to about 350 milligrams (mg) of magnesium (Mg) per gram (g) of dosage form, the dosage form comprising less than about 2.5% additives, and having a dissolution rate such that greater than about 80% of the active ingredient is dissolved within the first about 60 minutes after the dosage form enters the environment of use. In some embodiments, the dissolution rate is greater than about 80% within 30 minutes.

[0108] In some embodiments, each bead comprises a core and an active ingredient comprising magnesium. In some embodiments, suitable bead forms of magnesium comprise magnesium and threonate mixed with soluble components such as sugars (e.g., sucrose, mannitol, etc.), polymers (e.g., polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc.), surfactants (sodium lauryl sulfate, cremophor, tween, span, Pluronic, etc.), insoluble flow-promoting components (microcrystalline cellulose, calcium phosphate, talc, fumed silica, etc.), coating materials (examples of suitable coating materials are polyethylene glycol, hydroxypropyl methylcellulose, wax, fatty acid, etc.), dispersions in suitable materials (examples are wax, polymer, physiologically acceptable oil, soluble material, etc.), or combinations of the above.

[0109] 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 (Paulaur Cranbury, NJ). In some embodiments, the core has a particle size range of about 1 μm to about 1000 μm. In some embodiments, the core has a particle size range of about 300 μm to about 900 μm. In some embodiments, the core has a particle size range of about 450 μm to about 825 μm. In some embodiments, the core is coated to avoid interactions between the core and the active ingredient. For example, suitable coating materials include, but are not limited to, polyethylene glycol, hydroxypropyl methylcellulose, wax, fatty acids, and the like.

[0110] In some embodiments, the spheres comprise a portion of the dosage form ranging from about 50 mg / g to about 500 mg / g, such as from about 60 mg elemental magnesium / g dosage form (i.e., 60 mg Mg / g) to about 100 mg elemental magnesium / g dosage form (i.e., 100 mg Mg / g), etc. The percentage of beads will depend on the amount of additional components, if any, used in the dosage form.

[0111] The core may be coated with magnesium, such as magnesium threonate. In some embodiments, the magnesium threonate is present in an amount of about 150 mg / g (or 12.4 mg Mg / g) to about 950 mg / g (or 78.4 mg Mg / g), such as about 500 to 900 mg / g (or 41.2 to 74.3 mg Mg / g), based on the weight of the entire immediate release bead. In other embodiments, the magnesium is present in an amount of about 15 to 300 mg / g, such as about 25 to about 250 mg / g.

[0112] In some embodiments, magnesium threonate is added to the mixture of binder and glidant before coating the core. In some embodiments, the glidant is selected from, but not limited to, microcrystalline cellulose, calcium phosphate, talc, and fumed silica. The glidants may be used in amounts ranging from 1.5 mg / g to about 35 mg / g. In some embodiments, the glidant is in the range of about 1.5 mg / g to about 30 mg / g. In some embodiments, the glidant is in the range of about 2.5 mg / g to about 25 mg / g. In some embodiments, the glidant is in the range of about 5 mg / g to about 30 mg / g.

[0113] In some embodiments, the binder is selected from, but not limited to, povidone (PVP), croscarmellose, ethylcellulose, hydroxypropyl methylcellulose (HPMC, Opadry), hydroxypropyl cellulose (HPC), or combinations thereof. In some embodiments where the binder is HPMC, the binder is present in an amount ranging from about 15 mg / g to about 30 mg / g, such as from about 15 mg / g to about 25 mg / g. In some embodiments where the binder is povidone, the binder is present in an amount ranging from about 1.5 mg / g to about 35 mg / g, such as from about 5 mg / g to about 30 mg / g.

[0114] For example, the active ingredient and binder / water / glidant mixture may be prepared by mixing with a stirrer for at least 15 minutes, at least 30 minutes, or at least 1 hour. The components may also be combined by methods including blending, mixing, dissolving and evaporating, or by using a suspension.

[0115] In some embodiments, the active ingredient / binder / inert mixture is deposited, wet massed, extruded, granulated, or spray dried onto the cores. In some embodiments, the sugar spheres are pre-warmed to a temperature ranging from 40° C. to about 55° C. prior to application of the mixture. In some embodiments, the cores are coated with about 2% weight / weight (w / w) to about 10% w / w seal coating prior to application of the active layer. In some embodiments, the seal coating is any applicable coating capable of separating any active ingredient from the core, for example, a polymeric coating such as Eudragit®, HPMC, HPC, or combinations thereof.

[0116] In some embodiments, the sugar spheres are coated in a fluidized bed coater known in the art, such as, for example, a Glatt Powder Coater and Granulator, GPCG3 (Ramsey, NY). Coating conditions such as air velocity, spray rate, and spray pressure are generally controlled as recognized and known by those skilled in the art. In some embodiments, the temperature ranges from about 43° C. to about 51° C. In some embodiments, the air velocity ranges from about 5 to about 9 meters / second (m / s). The spray rate ranges from about 9 to about 42 grams / minute (g / min). The spray pressure can range from about 1.5 to about 2.0 bar. The beads are then dried in the fluidized bed of the coating apparatus at a temperature of about 45° C. to about 50° C. 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 different types of equipment can also be used.

[0117] Once the beads are formed as cores containing magnesium threonate as provided herein, they can be optionally further coated with a seal coating. In some embodiments, the seal coating is a polymer or combination of polymers that can be designed to be pH-dependent or independent. In some embodiments, the polymer for the seal coating is selected from, but not limited to, HPMC (Opadry®, Colorcon, Pa.), HPC, Eudragit® RL, Eudragit® E100, Eudragit® E12.5, Eudragit®, EPO, Eudragit® NE (e.g., NE30D or NE40D), 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 some embodiments, the beads are coated with a pH dependent polymer that is soluble at a pH such as a pH above 5. In immediate release bead formulations, the seal coating polymer is present in an amount ranging from about 0% w / w to about 40% w / w, such as from about 0% w / w to about 10% w / w, such as from about 0% w / w to about 3% w / w.

[0118] Alternatively, the core is coated with a coat that disintegrates or dissolves rapidly for aesthetic, handling or stability purposes. Suitable materials are polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, polymethacrylates containing free amino groups, each with or without plasticizers and with or without antiblocking or bulking agents. The addition of about 3% of the core weight as coating material is generally considered to provide a continuous coat for this size range. In some embodiments, the overcoating is HPMC (Opadry®, Colorcon, Pa.), HPC, Eudragit® RL, Eudragit® E100, Eudragit® E 12.5, Eudragit® E PO, Eudragit® NE and mixtures thereof.

[0119] In some embodiments, the beads or bead mixtures are used, for example, in a suspension, filled into a capsule, compressed into a tablet, or filled into a sachet. One or more types of sustained release beads may be mixed together and encapsulated or used as a sprinkle on the subject's food. In some embodiments, the oral solid dosage form is any of these forms. In some embodiments, the dosage form is a capsule. In some embodiments, the beads are formulated into a capsule by use of an encapsulation machine. Various capsule sizes may be required to accommodate strengths and meet the targeted formulation weight. The capsule size range is 00-5 to meet weights ranging from about 15 mg to about 630 mg.

[0120] The particle size of the immediate release and sustained release bead components in the dosage form depends on the technique used to prepare them. Particle size components range from submicron to 500 microns for powder techniques (mixing, spray drying, dispersion, etc.), 5 to 1700 microns for coating techniques (Wurster®, top spray, bottom spray, spray drying, extrusion, layering, etc.), and 1 to 40 millimeters (mm) for tableting techniques.

[0121] In addition to the active ingredients, including magnesium and threonate, the dosage form may contain any number of physiologically acceptable excipients, depending in part on the sustained release mechanism to be used. "Physiologically acceptable" includes molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to animals or humans, as appropriate, e.g., pharma- ceutical acceptable. "Physiologically acceptable carriers" include micelles, liposomes, microspheres, nanofibers, and any combination thereof. Physiologically acceptable carriers include any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for physiologically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the magnesium threonate composition is contemplated. Supplementary active ingredients may also be incorporated into the compositions. "Physiologically acceptable salts" include acid addition salts which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or organic acids such as acetic, oxalic, tartaric, mandelic, and the like. Salt forms formed with free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and from such organic bases as isopropylamine, trimethylamine, histidine, procaine, and the like. General techniques for formulation and administration can be found in "Remington: The Science and Practice of Pharmacy, Twentieth Edition," Lippincott Williams & Wilkins, Phil. Ladelphia, Pa. Tablets, capsules, pills, powders, granules, dolarges, gels, slurries, ointments, solutions, suppositories, injections, inhalants and aerosols are examples of such formulations.

[0122] For example, additional methods known in the art may be used to prepare sustained release oral formulations. For example, in some embodiments, a suitable sustained release form of the magnesium threonate composition provided herein is a matrix tablet or capsule composition. Suitable matrix forming materials include, for example, waxes (e.g., carnauba wax, beeswax, paraffin wax, ceresin, shellac wax, fatty acids and fatty alcohols), oils (e.g., hydrogenated vegetable oils), hydrogenated oils or fats (e.g., hydrogenated rapeseed oil, castor oil, beef tallow, palm oil and soybean oil) and polymers (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose and polyethylene glycol). Other suitable matrix tableting materials are microcrystalline cellulose, powdered cellulose, hydroxypropyl cellulose, ethyl cellulose with other carriers and fillers. In some embodiments, the tablet contains granules, coated powders or pellets. In some embodiments, the tablet is multi-layered. Multi-layered tablets are useful when different forms of active ingredients, such as magnesium and threonate, have significantly different pharmacokinetic profiles. The final finished tablets are optionally coated or uncoated.

[0123] The coating composition generally contains an insoluble matrix polymer (approximately 15-85% by weight of the coating composition) and a water-soluble material (e.g., approximately 15-85% by weight of the coating composition). Optionally, an enteric polymer (approximately 1-99% by weight of the coating composition) is 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, etc.), salts (e.g., sodium chloride, potassium chloride, etc.), 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, phthalates, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, and polymethacrylates containing carboxyl groups.

[0124] In some embodiments, the coating composition is plasticized according to the properties of the coating blend, such as the glass transition temperature of the major component or mixture of components or the solvent used to apply the coating composition. Suitable plasticizers may be added at 0-50% by weight of the coating composition, such as diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, acetylated citrate esters, dibutyl sebacate, and castor oil. Optionally, the coating composition may include a weighting agent. The amount of weighting agent may be 1% to approximately 99% by weight based on the total weight of the coating composition, and may be an insoluble material such as silicon dioxide, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, magnesium-containing compounds, or polacrilin potassium.

[0125] The coating composition may be applied as a solution or emulsion in an organic or aqueous solvent or mixtures thereof. If a solution is applied, the solvent may be present in an amount of approximately 25-99% by weight based on the total weight of dissolved solids. Suitable solvents are water, lower alcohols, lower chlorinated hydrocarbons, ketones or mixtures thereof. If an emulsion is applied, the solvent is present in an amount of approximately 25-97% by weight based on the amount of polymeric material in the emulsion. The solvent is primarily water. It could be.

[0126] In some embodiments utilizing a spray drying process, an aqueous dispersion of magnesium threonate and a compressibility enhancing agent (e.g., a surfactant or silicon dioxide) is combined with a sufficient volume of hot air to cause evaporation and drying of the droplets. The highly dispersed slurry can be pumped and atomized. It is atomized into a stream of warm filtered air, which provides heat for evaporation and conveys the dried product to a collection device. The air is then exhausted along with the moisture removed. The resulting spray dried powder particles can be approximately spherical and relatively uniform in size, thereby maintaining good flowability. The co-processed particles are not necessarily uniform or homogeneous. Other drying techniques such as flash drying, ring drying, micron drying, tray drying, vacuum drying, radio frequency drying, and possibly microwave drying can also be used.

[0127] Alternatively, all or a portion of the excipients may be subjected to wet granulation with the active ingredient. A typical wet granulation process includes loading the excipient particles into a suitable granulator, such as those available from Baker-Perkins, and granulating the particles with the active ingredient, such as using an aqueous granulation fluid. In some embodiments, a portion of the total amount of the excipients is wet granulated with the active ingredient, and then an additional portion of the excipients is added to the granulation. In other embodiments, depending on the requirements of a particular formulation, the additional portion of the excipients to be added to the excipient / active ingredient granulation may of course be replaced with other excipients commonly used by those skilled in the art.

[0128] The entire mixture may then be subjected to compression in a conventional production-scale tablet press in an amount sufficient to produce a uniform batch of tablets at normal compression pressures for that machine, e.g., about 1500 to 10,000 pounds per square inch (lbs / sq in). The compression of the mixture should be such that there is no difficulty in hydrating it when subsequently exposed to gastric fluids.

[0129] In some embodiments, the compositions described herein are prepared using formulations such as those described in U.S. Pat. Nos. 4,606,909, 4,769,027, 4,897,268, 5,395,626, 6,919,373, 6,923,800, 6,929,803, 6,939,556, 6,797,283, 6,764,697, and 6,635,268.

[0130] In addition to oral dosage forms, the composition can be administered to a subject by any available and effective delivery system. Such delivery systems include, but are not limited to, parenteral, transdermal, intranasal, sublingual, transmucosal, intraarterial or intradermal administration modes in dosage unit formulations containing conventional non-toxic and physiologically acceptable carriers, adjuvants and vehicles as necessary, such as depot or controlled release formulations. Depending on the route of administration, the composition can be formulated as a suppository, lotion, patch or device (e.g., subcutaneously implantable delivery device or inhalation pump). The composition can be optimized for a specific type of delivery.

[0131] In some embodiments, magnesium threonate is delivered in aerosol spray formulation from a pressurized pack, nebulizer or dry powder inhaler.Suitable propellants that can be used in nebulizer include, for example, dichlorodifluoro-methane, trichlorofluoromethane, dichlorotetrafluoroethane and carbon dioxide.Dosage can be determined by providing a valve to deliver a regulated amount of compound in the case of pressurized aerosol.

[0132] Compositions for inhalation or insufflation may be prepared in the form of solutions in pharma- ceutical acceptable aqueous or organic solvents, and The compositions include, but are not limited to, liquids, suspensions or mixtures thereof, and powders. Liquid or solid compositions may contain suitable excipients as set forth above. Compositions in acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

[0133] In some embodiments, the compositions may be administered transdermally, e.g., as generally described in U.S. Patent Application Nos. 5,186,938 and 6,183,770, 4,861,800, 6,743,211, 6,945,952, 4,284,444, and WO 89 / 09051.

[0134] In some embodiments, the compositions may be delivered to the brain via intranasal, buccal, or sublingual routes rather than by inhalation to allow for the transfer of active agents to the CNS via the olfactory pathway and reduced systemic administration. Devices commonly used for this route of administration are included in U.S. Patent No. 6,715,485.

[0135] Preparation of compositions for delivery in a subcutaneously implantable device may be carried out using methods known in the art, such as those described in, for example, U.S. Patent Application Nos. 3,992,518; 5,660,848; 5,756,115; 5,422,123; 5,601,845; 5,912,013; and 6,194,000. EXAMPLES

[0136] Example 1 An example of a fast-release tablet (Formulation A) is discussed. Formulation A tablet contains magnesium L-threonate (450 mg) as a magnesium composition, carnauba wax as a binder, magnesium stearate as a lubricant, and an aqueous moisture-proof coating. The weight ratio of carnauba wax to magnesium stearate is 12.

[0137] [Table 2]

[0138] The release profile of the above-prepared Formulation A tablets was investigated in a USP Type II (paddle) dissolution system at 75 rpm in 0.1N HCl (pH 1.1) or acetate buffer (pH 4.5) at a temperature of about 37° C. The amount of threonic acid released over time was measured using HPLC. The release profiles at pH 1.1 and 4.5 are shown in FIG. 7.

[0139] Example 2 Preparation and dissolution profile of extended release tablets An example of sustained release tablet (Formulation B) is discussed. Formulation B tablet, sustained release tablet, contains magnesium L-threonate as magnesium composition, carnauba wax as binder, magnesium stearate as lubricant and coating containing talc as inert powder and hardened vegetable oil. The weight ratio of carnauba wax to magnesium stearate is 20. A formulation with 450mg magnesium L-threonate with other excipients being the same was also prepared.

[0140] [Table 3]

[0141] The release profile of the above prepared Formulation B tablets was investigated in a USP Type II (paddle) dissolution system at 75 rpm in 0.1N HCl (pH 1.1), acetate buffer (pH 4.5) or phosphate buffer (pH 6.8) at a temperature of about 37° C. The amount of threonic acid released over time was measured using HPLC. The release profiles at pH 1.1 (represented as 114), 4.5 (represented as 124) and 6.8 (represented as 144) are shown in Figures 1A, 1B and 1C.

[0142] Example 3 Preparation and dissolution profile of controlled release tablets Another example of a sustained release tablet formulation (Formulation C) is discussed. Formulation C tablet, a controlled release tablet, contains magnesium L-threonate, povidone K-90 as a binder, microcrystalline cellulose as a glidant, colloidal silicon dioxide as a filler, carbopol and carboxymethylcellulose as swelling materials, Starcap starch as an inert powder, magnesium stearate lubricant and talc.

[0143] [Table 4]

[0144] The release profile of the above prepared Formulation C tablets was investigated in a USP Type II (paddle) dissolution system at 75 rpm in 0.1N HCl (pH 1.1) or acetate buffer (pH 4.5) at a temperature of about 37° C. HPLC was used to measure the amount of threonate released over time. ICP-MS was used to measure the amount of magnesium released over time. The release profiles at pH 1.1 (represented as 116) and 4.5 (represented as 126) are shown in Figures 1A, 1B, and 1D.

[0145] Example 4 Pharmacokinetic study of magnesium threonate dosage This example compares the fluctuation index of three dosage forms (Formulation A, Formulation B and Formulation C) containing magnesium threonate. Compared with the immediate release dosage form (Formulation A), the sustained release dosage forms (Formulation B and Formulation C) are intended to promote slower release of the active substance (magnesium and / or threonate). The sustained release dosage forms are intended to provide an exposure of the active substance sufficient for administration once or twice a day.

[0146] Subjects and methods The concentration of L-threonic acid in plasma of subjects administered with a single dosage form (3 tablets) of Formulation A, Formulation B or Formulation C was determined by HPLC. Twelve male subjects were given 1350mg or 1500mg of Formulation A, Formulation B and Formulation C in a randomized crossover fashion (separated by a 3-day washout period). Plasma was collected from subjects administered with a single dosage form in a fasting or fed state after a full meal. Fourteen plasma samples were collected over a 24-hour period for each subject administered with the dosage form.

[0147] PK curves were generated to assess total magnesium L-threonate exposure over 24 hours (AUC 0-24 ), peak plasma concentration of L-threonic acid (C max ), and the time to reach peak plasma concentration of L-threonate (T max ) and terminal half-life (T 1 / 2 ) to calculate Plasma concentrations were used to determine the mean AUC. Values ​​given in Table 2 are the average of all subjects who completed dosing with all three formulations. 0-24 and C max Values ​​were normalized to an effective dose of 1500 mg. Any AUC from subjects receiving the 1350 mg dosage form (3 tablets each containing 450 mg magnesium L-threonate) 0-24 Or C max Multiply the value by 10 and divide by 9. max and T max are both observed and not calculated. In other words, for each subject, the maximum analytical concentration is C max and the corresponding time is T maxUsing all time points for which plasma concentrations were available from 0 to 24 hours, the AUC 0-24 We calculated T 1 / 2 The following formula was used to calculate:

number

[0148] To calculate the gains and losses and skewness of each curve, a virtual steady-state graph was created every 12 hours to simulate repeated dosing. Concentration data from the first 12 hours after dosing (dose interval) were used to calculate the fluctuation index. The estimated fluctuation of the plasma concentration of L-threonate was calculated by subtracting the steady-state minimum concentration from the steady-state maximum concentration. Theoretically, a steady state was achieved by approximately 24 hours.

[0149] Skewness, a characteristic of the degree of asymmetry of a distribution around its mean, was calculated using the Excel SKEW function. Positive skewness indicates a distribution with asymmetric tails extending towards more positive values, and negative skewness indicates a distribution with asymmetric tails extending towards more negative values. To use the Excel SKEW function, the x-axis needs to be uniformly distributed. Therefore, y-values ​​were estimated for x-values ​​at 1-hour intervals over a 12-hour period (hours 12-36 from the steady-state curve).

[0150] [Table 5]

[0151] Table 3 shows the concentrations adjusted to be the therapeutic dose for patients. The top table shows data from a pharmacokinetic study (24 mg / kg LBM / dose). Table 3 shows the adjusted values ​​for 17.5 mg / kg LBM / dose.

[0152] [Table 6]

[0153] Example 5 Dose Estimation This example compares the dosage of magnesium L-threonate provided in the dosage form. The effect of magnesium L-threonate treatment on human cognitive performance was evaluated by thresholds based on each subject's total body weight (TBW) and each subject's lean body mass (LBM).

[0154] In two studies, male and female human subjects were given a dosage form containing magnesium L-threonate daily for 9-12 weeks. In the first study, the dosage of the dosage form was set to correspond to approximately 1.5 g magnesium L-threonate / day (1.5 g / day) for subjects with TBW of 50-70 kg, and approximately 2 g magnesium L-threonate / day (2 g / day) for subjects with TBW of 70-100 kg. Male and female subjects aged 50-70 years were administered magnesium L-threonate for 12 weeks. After administration of magnesium L-threonate, the following subjects were administered magnesium L-threonate daily: Efficacy in improving global cognition was determined by changes in performance on a neuropsychological test battery (NTB) consisting of four validated cognitive tests including function, working memory, attention, and episodic memory. The NTB score can be expressed as a composite score of the combined standardized scores (z-scores) of the clinical trial population from the individual cognitive tests.

[0155] In the second study, male and female patients with schizophrenia aged 18-55 years were given 2 grams of magnesium L-threonate per day (2g / day). After 9 weeks of magnesium L-threonate treatment, efficacy in improving global cognition was determined by change in performance on the MATRICS Consensus Cognitive Battery (MCCB). The MCCB can also be expressed as a z-score.

[0156] To evaluate the overall effect of magnesium L-threonate in the two studies, the data from the two studies were combined using z-score change from baseline. Subjects were divided into high and low dose groups based on the median dose / day by TBW and by LBM for all subjects in both studies. The median dose / day by TBW was approximately 24mg / kg TBW / day, and the median dose / day by LBM was approximately 35mg / kg LBM / day. When subject scores were divided according to high and low doses by TBW, subjects receiving high doses of the drug (>24mg / kg TBW / day) did not perform better than subjects receiving low doses of the drug (<24mg / kg TBW / day) (Figure 4, plot 410). Additionally, when subjects were separated by high and low LBM doses, subjects receiving high doses of the drug (>35 mg / kg LBM / day) showed significantly greater improvement in overall cognitive performance than subjects receiving low doses of the drug (<35 mg / kg LBM / day) (Figure 4B, plot 420).

[0157] A two-sample T-test was used to compare efficacy in the low-dose and high-dose groups based on TBW and LBM. As shown in Table 4, there was no difference in efficacy between the low-dose and high-dose groups based on TBW (p=0.81). However, as shown in Table 5, when adjusted for LBM, the efficacy of the high-dose group was significantly higher than that of the low-dose group (p=0.02). These data indicate that the dose should be adjusted for LBM.

[0158] [Table 7]

[0159] [Table 8]

[0160] Example 6 Improved mood and cognition This example compares the in vivo efficacy of two dosage forms (Formulation A and Formulation B) containing magnesium threonate, which show different in vivo plasma concentration profiles.Formulation B shows lower fluctuation index and lower skewness compared to Formulations A and C disclosed herein.The two dosage forms are compared for mood and cognition improvement in human subjects.

[0161] Subjects and methods A single-center, double-blind, four-period crossover study was conducted in 22 healthy male and female subjects aged 35-72 years (all ages included). Consenting subjects completed online questionnaires to assess subjects' sleep, mood, and cognitive performance. Subjects with subjective sleep and mood complaints were included. Sleep complaints were required to include problems with sleep maintenance.

[0162] Dosage was based on subjects' lean body mass (LBM). Dosage was a single dose of approximately 20 mg / kg LBM / day (half of the daily dose of 40 mg / kg LBM / day), for nighttime administration only. Subjects received either magnesium L-threonate or placebo in random order for 5 days, each separated by a 2-day washout. Each study period, including the washout, lasted 1 week. Period A: Baseline (1 week off treatment) Period B: Magnesium L-threonate formulation A (1-3 450 mg tablets) was administered once at night. Period C: Placebo matching regimen A Period D: Magnesium L-threonate formulation B (1 to 3 450 mg tablets) was administered once at night. Period E: Placebo matching Formulation B

[0163] The study duration was 35 days (last calendar entry on days 1-35). Subjects completed daily sleep and mood diaries in the morning and evening and at the end of each dosing period (before washout), and subjects completed a computerized neuropsychological test battery (NTB). The cognitive tests included in the NTB were the Trail Making Test (TMT), Digit Span Test (retrospective), and Digit Sign Substitution Test (DSST).

[0164] Daily sleep diaries included morning questions about sleep quality and refreshment and evening questions about mood (anxiety and depression) and external factors influencing mood (emotional events and workload). All diaries were completed online each day within one hour of going to bed and waking up. Cognitive testing was completed online on the sixth day of each study period.

[0165] statistical methods Data analysis included 15 subjects who completed the study, were dosed, and adhered to the protocol throughout the study. Individual cognitive test scores were converted to standardized z-scores. Study population baseline values ​​were used to calculate z-scores. Subject z-scores from the three studies were averaged at each time point to create a subject composite cognitive score. Cognitive composite scores across the five periods (baseline and four dosing periods) for all subjects were compared using multilevel linear models. A general linear model was used with treatment as a fixed factor and age, sex, and mood as covariates (SPSS Statistics Subscription). Anxiety and depression questions in the daily sleep diary were converted to z-scores for each subject using all values ​​for each subject. Anxiety and depression scores were calculated for each period by averaging days 3-5. Anxiety and depression z-scores were averaged for each study period for each subject to create mood z-scores. Mood scores for the different treatments (baseline, mgT formulation A, formulation B, placebo A, placebo B) were compared by multilevel linear models in which treatment was the fixed factor and daily emotional arousal, workload, and sleep quality were covariates. P less than 0.05 was considered significant. The results of this study are shown in Figures 5A-5C.

[0166] Example 7 Tablet preparation and dissolution profile Another example of a tablet dosage form (Formulation D) was prepared having two parts intragranular and extragranular components as shown in Table 6.

[0167] [Table 9]

[0168] Tablets are prepared by pre-blending each of parts 1 and 2 of the intragranular components. Each part is then subjected to roller compaction to combine the parts. The extragranular portion is then added and tablets are formed using a production scale tablet press at normal compression pressures.

[0169] The release profile of the above prepared Formulation D tablets was investigated in a USP Type II (paddle) dissolution system at 75 rpm in 0.1N HCl (pH 1.1) or acetate buffer (pH 4.5) at a temperature of about 37° C. HPLC was used to measure the amount of threonic acid released over time. The release profile is shown in FIG. 6.

[0170] Another example of a tablet dosage form (Formulation D) was prepared having some intragranular and extragranular components as shown in Table 7.

[0171] [Table 10]

[0172] Table 8 provides the dissolution data for the above formulations.

[0173] [Table 11]

[0174] 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. The present invention is not limited by the specific examples provided in the document. Although the present invention has been described with reference to the above specification, the description and illustration of the embodiments herein are not to be construed in a limiting sense. Numerous variations, changes and substitutions will occur to those skilled in the art without departing from the present invention. Furthermore, it will be understood that all aspects of the present invention are not limited to the specific depictions, configurations or relative proportions shown herein, which depend on various conditions and variables. It is understood that various alternatives to the embodiments of the present invention described herein may be used in the practice of the present invention. It is therefore contemplated that the present invention encompasses any such alternatives, modifications, variations or equivalents. The following claims define the scope of the present invention, and methods and structures within the scope of these claims and their equivalents are intended to be covered thereby.

Claims

1. A dosage form comprising magnesium threonate for the treatment of a disease, disorder, syndrome and / or condition in a patient in need thereof, comprising: (a) At least a portion of the magnesium (Mg) and threonate (T) in the magnesium threonate is MgT ２ and (b) the magnesium threonate is present in an amount of about 200 to 6000 mg; (c) when administered to a patient in need thereof, the dosage form has a mean C ａｖｇ The dosage form is sufficient to provide an in vivo plasma profile of threonic acid comprising:

2. 10. The dosage form of claim 1, wherein the in vivo plasma profile from the dosage form exhibits a variation index that is less than about 170%.

3. The in vivo plasma profile from the dosage form has a mean T ｍａｘ The dosage form according to claim 1 or 2, wherein

4. A dosage form comprising magnesium threonate, (a) At least a portion of the magnesium (Mg) and threonate (T) in the magnesium threonate is MgT ２ and (b) the magnesium threonate is present in an amount of about 200 to 6000 mg; and (c) an in vivo plasma profile from said dosage form exhibits a variation index that is less than about 170%.

5. 5. The dosage form of any one of claims 1 to 4, wherein the in vivo plasma profile from the dosage form exhibits a skewness that is less than about 0.

2.

6. A dosage form comprising magnesium threonate, (a) At least a portion of the magnesium (Mg) and threonate (T) in the magnesium threonate is MgT ２ and (b) the magnesium threonate is present in an amount of about 200 to 6000 mg; and (c) an in vivo plasma profile from said dosage form exhibits a skewness that is less than about 0.

2.

7. A dosage form comprising magnesium threonate, (a) At least a portion of the magnesium (Mg) and threonate (T) in the magnesium threonate is MgT ２ and (b) the magnesium threonate is present in an amount of about 200 to 6000 mg; and (c) The release of said magnesium threonate from said dosage form is calculated from measurements obtained using a USP Type II (paddle) dissolution system at a temperature of about 37° C. and 75 rpm for about 0.2 h. －１ ~0.6h －１ A dosage form exhibiting a first order release constant of.

8. The first order release constant is about 0.25 h －１ ~0.45h －１ 8. The dosage form of claim 7,

9. The first order release constant is about 0.3 h －１ ~0.4h －１ 8. The dosage form of claim 7,

10. The dosage form according to any one of claims 1 to 9, which is administered orally to the patient.

11. The dosage form according to any one of claims 1 to 10, which is administered to a patient in a fed state.

12. The dosage form of any one of claims 1 to 11, given every 12 hours, is sufficient to provide at least about 15 mg / kg of lean body mass / dose of magnesium threonate in a patient in need of treatment for a disease, disorder, syndrome and / or condition.

13. The dosage form of any one of claims 1 to 12, given every 12 hours, is sufficient to provide about 10-30 mg / kg of lean body mass / dose of magnesium threonate in a patient in need of treatment of a disease, disorder, syndrome and / or condition.

14. The dosage form of any one of claims 1 to 12, sufficient to provide at least about 15 mg / kg of lean body mass / dose / day of magnesium threonate in a patient in need of treatment of a disease, disorder, syndrome and / or condition.

15. 13. The dosage form of any one of claims 1 to 12, sufficient to provide about 20-60 mg / kg of lean body weight / day of magnesium threonate.

16. 13. The dosage form of any one of claims 1 to 12, sufficient to provide at least about 30 mg / kg of lean body mass / day of magnesium threonate.

17. 17. The dosage form of any one of claims 1 to 16, wherein the magnesium threonate is present in an amount of about 40 to about 77% wt / wt.

18. 18. The dosage form of any one of claims 1 to 17, wherein the magnesium threonate is present in an amount of about 45 to about 70% wt / wt.

19. 20. The dosage form of claim 18, wherein the magnesium threonate is present in an amount of about 70%.

20. 20. The dosage form of claim 18, wherein the magnesium threonate is present in an amount of about 53%.

21. 21. The dosage form of any one of claims 1 to 20, further comprising carnauba wax.

22. 22. The dosage form of claim 21, wherein the carnauba wax is present in an amount of about 10 to about 30% wt / wt.

23. 23. The dosage form of claim 22, wherein the carnauba wax is present in an amount of about 10% wt / wt.

24. 23. The dosage form of claim 22, wherein the carnauba wax is present in an amount of about 28% wt / wt.

25. 25. The dosage form of any one of claims 1 to 24, further comprising magnesium stearate.

26. 26. The dosage form of claim 25, wherein the magnesium stearate is present in an amount of about 1% to about 3% wt / wt.

27. 26. The dosage form of claim 25, wherein the magnesium stearate is present in an amount of about 1% to about 2% wt / wt.

28. 26. The dosage form of claim 25, wherein the magnesium stearate is present in an amount of about 1.4% wt / wt.

29. 26. The method of claim 25, wherein the magnesium stearate is present in an amount of about 2% wt / wt. The dosage form listed above.

30. 26. The dosage form of claim 25, wherein the weight ratio of said carnauba wax to said magnesium stearate is greater than about 12.

31. 26. The dosage form of claim 25, wherein the weight ratio of said carnauba wax to said magnesium stearate is about 20.

32. 32. The dosage form of any one of claims 1 to 31, comprising an intragranular portion and an extragranular portion.

33. 26. The dosage form of claim 25, wherein the weight ratio of said carnauba wax to said magnesium stearate in said intragranular portion is from about 5 to about 12.

34. 34. The dosage form of claim 33, wherein the weight ratio of said carnauba wax to said magnesium stearate in said intragranular portion is about 8.

35. 34. The dosage form of claim 33, wherein the weight ratio of said carnauba wax to said magnesium stearate in said intragranular portion is about 10.

36. 36. The dosage form of any one of claims 1 to 35, which is liquid, semi-liquid, semi-solid or solid.

37. 36. The dosage form of any one of claims 1 to 35 which is a gel, pill, tablet, capsule, bead, emulsion, granule, paste, pellet, powder, syrup, suspension, slurry or aerosol.

38. 38. The dosage form of any one of claims 1 to 37, further comprising an additional substance.

39. 40. The dosage form of claim 38, wherein the additional substance is a pharma- ceutically acceptable excipient.

40. 40. The dosage form of claim 39, wherein the pharma- ceutically acceptable excipient is selected from the group consisting of binders, fillers, lubricants, solubilizers, and any combination thereof.

41. 40. The dosage form of claim 39, wherein the pharma- ceutically acceptable excipient is selected from the group consisting of lactose, microcrystalline cellulose, silicon dioxide, titanium dioxide, stearic acid, starch, sodium starch glycolate, povidone, pregelatinized starch, croscarmellose, ethylcellulose, dicalcium phosphate, talc, sucrose, calcium stearate, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, hydrogenated vegetable oil, beeswax, and any combination thereof.

42. A method of treating a disease, disorder, syndrome and / or condition in a patient in need thereof, comprising orally administering a dosage form according to any one of claims 1 to 38.

43. The dosage form provides at least about 15 mg / kg of lean body mass / dose of MgT to a patient having a disease, disorder, syndrome, and / or condition. ２ 43. The method of claim 42, wherein said method is sufficient to provide

44. (a) determining a physiological concentration of threonate in said patient prior to administering said dosage form; (b) determining at least one additional physiological concentration of threonate in the patient after oral administration of the dosage form; 44. The method of claim 42 or 43, further comprising:

45. 45. The method of claim 44, wherein the physiological concentration is in a serum concentration, a plasma concentration, a urine concentration or a cerebrospinal fluid concentration.

46. 46. ​​The method of any one of claims 42 to 45, wherein the dosage form is administered twice daily with food.

47. 46. ​​The method of any one of claims 42 to 45, wherein the patient is suffering from a disease, disorder, syndrome and / or condition selected from cardiovascular disease, neurodegenerative disorder, sleep disorder, neurological disorder, neurological injury, developmental disorder / autism spectrum disorder, autoimmune disease, genetic disorder, rheumatic disease, inflammatory disease, neuropsychiatric disorder, cancer, addiction and physical trauma.

48. 48. The method of any one of claims 42 to 47, wherein the disease, disorder, syndrome and / or condition is selected from mild cognitive impairment, short-term memory loss, long-term memory loss, Alzheimer's disease, Parkinson's disease, Huntington's disease, autism, schizophrenia, cognitive decline, depression, dementia, attention deficit hyperactivity disorder (ADHD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetes, cardiovascular disease, hypertension, migraine, glaucoma, mood disorders, stress, anxiety, depression, sleep disorders, psychosis, metabolic disorders, fatigue, cancer, HIV, hepatitis, spinal cord injury, post-operative recovery, post-traumatic stress disorder, arthritis, neuropathic pain, inflammation, tremor and fibromyalgia.

49. A method of making a dosage form according to any one of claims 1 to 41, comprising the steps of: (a) forming a mixture comprising the magnesium threonate and an additional substance, wherein at least a portion of the magnesium (Mg) and threonate (T) of the magnesium threonate is MgT ２ and forming a salt of (b) formulating the mixture to form the dosage form; The method includes:

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