Magnesium threonate composition and application thereof

Abstract

Dosage forms comprising magnesium threonate with enhanced efficacy are provided. The pharmacokinetic profile of magnesium threonate with enhanced efficacy is also provided. These dosage forms and pharmacokinetic profiles of magnesium threonate are useful for the treatment of a variety of diseases, disorders, syndromes and / or conditions.

Description

[0001] This application is a divisional application of the invention patent application with the application date of April 24, 2019, the application number of 201980042120.9, and the invention name of "Magnesium threonate composition and its use".

[0002] Magnesium is one of the most abundant minerals in the human body and plays multiple roles in maintaining good health. Examples of the roles of magnesium in living cells include the homeostasis of other minerals such as sodium, potassium, and calcium, as well as the formation, transfer, storage, and utilization of adenosine triphosphate (ATP), which is the main energy source in living cells. Other functions of magnesium in the human body include maintaining normal muscle and nerve activities, heart rhythm, bone strength, and immune system health.

[0003] It is estimated that most people in the United States may not consume enough magnesium and may therefore be magnesium deficient. Magnesium deficiency, including hypomagnesemia, refers to insufficient intake of magnesium in the diet or impaired absorption of magnesium. Magnesium deficiency is also associated with many symptoms and diseases, including hypertension, atherosclerosis, arrhythmia, diabetes, and metabolic syndrome. Magnesium deficiency may also be related to neurological disorders including dementia, Alzheimer's disease, and depression.

[0004] Generally, magnesium compounds have low bioavailability and are not efficient in increasing the magnesium concentration in the central nervous system (CNS). However, magnesium threonate has high bioavailability relative to other magnesium compounds and is uniquely able to significantly increase the magnesium concentration in the CNS. Specifically, magnesium threonate can increase the magnesium concentration at neuronal synapses, which is important for proper synaptic function and nerve function. Studies have confirmed that magnesium threonate can relieve many diseases, disorders, syndromes, and conditions. For example, it can improve learning and memory, reduce neuropsychiatric symptoms, relieve neuropathic pain, and prevent cancer cell growth and migration. Summary of the Invention

[0005] There is provided a dosage form comprising magnesium threonate for treating a disease, disorder, syndrome, or condition in a patient in need thereof, wherein:

[0006] (a) At least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the form of the salt MgT2;

[0007] (b) Magnesium threonate is present in an amount between about 200 and 6000 mg;

[0008] (c) When administered to a patient in need thereof, the dosage form is sufficient to provide a certain in vivo plasma profile of threonic acid, the in vivo plasma profile including an average C between about 5 μg / mL and about 20 μg / mL avg .

[0009] There is also provided a dosage form comprising magnesium threonate, wherein:

[0010] (a) At least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the form of the salt MgT2;

[0011] (b) Magnesium threonate is present in an amount between about 200 and 6000 mg; and

[0012] (c) The in vivo plasma profile from the dosage form exhibits a fluctuation index of less than about 170%.

[0013] There is also provided a dosage form comprising magnesium threonate, wherein:

[0014] (a) At least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the form of the salt MgT2;

[0015] (b) Magnesium threonate is present in an amount between about 200 and 6000 mg; and

[0016] (c) The release of magnesium threonate from the dosage form exhibits a first-order release constant between about 0.2 h -1 and 0.6 h -1 which is calculated from measured values obtained using a USP type II (paddle) dissolution system at 75 rpm at a temperature of about 37 °C.

[0017] There is also provided a dosage form comprising magnesium threonate, wherein:

[0018] (a) At least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the form of the salt MgT2;

[0019] (b) Magnesium threonate is present in an amount of about 17.5 mg / kg LBM / dose; and

[0020] (c) When administered to a patient in a fed state, the dosage form is sufficient to provide a certain in vivo plasma profile of threonic acid, which in vivo plasma profile includes:

[0021] (i) A 24-hour average AUC (AUC 0-24 ) of at least about 70 μg·h / mL;

[0022] (ii) An average C max of less than about 13 μg / mL.

[0023] There is also provided a method of treating a disease, disorder, syndrome or condition using the dosage form described herein.

[0024] There is also provided a method for preparing the dosage form described herein.

[0025] These and other aspects of the invention will become apparent when referring to the following detailed description. To this end, all publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference in their entirety as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The novel features of the invention are set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by reference to the following detailed description and the accompanying drawings (also referred to herein as "figures"), which set forth illustrative embodiments that utilize the principles of the invention and are in the appended

[0027] In the figures:

[0028] Figure 1A-1D Shows the threonic acid dissolution curve of a dosage form containing magnesium threonate.

[0029] Figure 2A-2F Shows the plasma concentration curve of a dosage form containing magnesium threonate.

[0030] Figure 3 Shows the model plasma concentration curve of theoretical repeated dosing of a dosage form containing magnesium threonate.

[0031] Figure 4 Illustrates the neuropsychological battery test z-scores of patients treated with magnesium threonate based on total body weight (TBW) dose or lean body mass (LBM) dose.

[0032] Figure 5A-5C Illustrates the mood (anxiety and depression z-scores), overall cognition (composite z-score consisting of working memory, processing speed, and cognitive flexibility), and working memory (digit span backwards) of human subjects orally administered a dosage form containing magnesium threonate, respectively.

[0033] Figure 6 Shows the threonic acid dissolution curve of a dosage form containing magnesium threonate.

[0034] Figure 7 Shows the threonic acid dissolution curve of a dosage form containing magnesium threonate.

[0035] Figure 8 Shows the dose-response curve of magnesium threonate. DETAILED DESCRIPTION

[0036] Although the preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0037] In the following description, certain specific details are set forth in order to provide a thorough understanding of the embodiments. However, those skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail so as not to unnecessarily obscure the description of the embodiments. Unless the context otherwise requires, throughout the following specification and claims, the word “comprise” and variations thereof (such as “comprises” and “comprising”) shall be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0038] Throughout the specification, reference to “one embodiment” or “an embodiment” or “some embodiments” or “a certain embodiment” means that a particular feature, structure, or characteristic described in connection with the 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 certain embodiment” throughout the specification are not necessarily all referring to the same embodiment. Moreover, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0039] Likewise, as used in this specification and the appended claims, unless the context clearly dictates otherwise, the singular forms “a / an” and “the” include plural referents.

[0040] Generally, the term “magnesium threonate” refers to the salt form of MgT2, as shown in the formula provided below:

[0041]

[0042] Magnesium threonate may also be referred to as magnesium L-threonate, magnesium (2R,3S)-2,3,4-trihydroxybutanoate, magnesium L-threonate salt (L-TAMS), MgT, or magtein.

[0043] Generally, the term "threonate" means threonate and / or a threonate precursor.

[0044] Generally, the term "threonate precursor" means a precursor molecule that can be readily converted to threonate when the composition is dissolved in an aqueous medium or is taken up due to ionization or hydrolysis, with or without the assistance of an enzyme. The precursor can be an ester derivative of threonic acid, threose, or threonate, or lactonized threonic acid. Generally, threonate refers to L-threonate. For example, an L-threonate precursor is L-threonic acid, an ester derivative of L-threonic acid or L-threonate, or lactonized L-threonic acid. In some embodiments, D-threonate or its precursor is used.

[0045] Generally, the term "elemental magnesium" as used in conjunction with the magnesium counterion compounds described herein refers to the total amount of magnesium present as free ions and magnesium bound to one or more counterions. Generally, this term is not used to refer to magnesium associated with reagents other than magnesium counterion compounds, which are components of magnesium counterion compositions (e.g., pharmaceutical compositions, dietary supplement compositions, foods supplemented with magnesium counterion compounds). Small amounts of magnesium may be naturally present in or otherwise associated with such reagents. For example, fruit juice extracts or flavorings may contain an amount of magnesium that is derived from the magnesium naturally present in the fruit from which they are sourced.

[0046] Generally, the term "bioavailability" refers to the rate and extent to which an active agent or its active form is absorbed from a pharmaceutical product (e.g., an oral dosage form) and becomes available at the site of action. See U.S. Code of Federal Regulations, Title 21, Part 320.1 (2001 edition). For oral dosage forms, bioavailability generally involves the release of the active ingredient from the oral dosage form (e.g., a tablet), conversion to the active form (if the active agent is not already in the active form), and movement to the site of action (e.g., absorption into the systemic circulation). Variations in the drug bioavailability attributable to an oral dosage form 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). The AUC can be a comprehensive measure of the systemic drug concentration over time, expressed in units of mass-time / volume (e.g., micrograms-hour / mL or μg-hour / ml). Alternatively or in addition, the AUC can be a comprehensive measure of the systemic drug concentration over a defined measurable time period. The AUC within the first 12 hours or 24 hours after administration of an oral dosage form is referred to as AUC 0-12 or AUC 0-24 .

[0047] Generally, the term C maxRefers to the peak plasma concentration of a drug.

[0048] Generally, the term T max Refers to the time to reach the peak plasma concentration.

[0049] Generally, the term T 1 / 2 Or the terminal half-life refers to the time required to divide the plasma concentration of a drug by 2 after reaching pseudo-equilibrium.

[0050] Generally, the term "cognition" refers to the process of acquiring, organizing, understanding, processing, and / or using information or knowledge. Generally, enhancing cognitive function refers to enhancing any aspect of this process, such as learning, the execution of mental operations, the storage, retrieval, and / or use of information and / or thoughts, memory, and / or preventing, for example, a decline in the cognitive state of a subject. Various standardized tests can be used to evaluate cognition, cognitive function, and / or cognitive state, and can be used to identify subjects who may contribute to, benefit from, and / or require the maintenance and / or enhancement of cognition, cognitive function, and / or cognitive state, and / or to monitor the therapeutic effects related to cognition, cognitive function, and / or cognitive state. Examples of suitable tests include the Mini-Mental State Examination (Folstein, 1975), components of the PROSPER neuropsychological test battery (Houx, 2002), and / or similar tests. Family history, age, and / or other factors can also be used to identify subjects who may contribute to, benefit from, and / or require the maintenance and / or enhancement of cognition, cognitive function, and / or cognitive state.

[0051] Generally, the "dissolution profile" at a given time, i.e., the degree of release of magnesium and / or threonic acid over the expected time, can be conveniently determined by measuring the release amount under controlled conditions, e.g., using a USP dissolution apparatus. Preferred release profiles are those that slow the rate of uptake of threonic acid and / or magnesium into the bloodstream while providing a therapeutically effective level of release of threonate and / or magnesium. According to the standardized dissolution test guidelines for extended release profiles, the dissolution of the active ingredient is measured at given time intervals over a period of time. At least three time points are recommended, which typically cover the early, middle, and late stages of the dissolution profile. The last measurement should be no earlier than the time point at which at least 80% of the active ingredient has dissolved (Guidance for Industry, "Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro / In Vivo Correlations", Food and Drug Administration, CDER, September 1997, page 17). Adequate sampling is important: e.g., at 1, 2, and 4 hours and then every two hours thereafter until 80% of the active ingredient has been released (Guidance for Industry, SUPAC-MR: Modified Release Solid Oral Dosage Forms, Food and Drug Administration, CDER, September 1997, page 6). Preferred dissolution apparatuses are the USP I (basket) or II (paddle) devices, which are used at recognized speeds, e.g., 100 revolutions per minute (rpm) for the basket and 50 - 75 rpm for the paddle (Guidance for Industry, "Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro / In Vivo Correlations", Food and Drug Administration, CDER, September 1997, page 4). Extended release dosage forms permit the release of the active ingredient over a longer period of time.On the other hand, a material that will be at least 80% dissolved in solution within the first 30 to 60 minutes meets the immediate release (IR) profile ("Dissolution Testing of Immediate Release Solid Oral Dosage Forms", published August 1997, Section IV-A).

[0052] In general, the term "dose proportionality" as used herein refers to the relationship between the dose of an active ingredient and its bioavailability. For example, if twice the same composition will deliver twice the active ingredient and provide the same bioavailability as one dose of the dosage form, then dose proportionality exists. Dose proportionality applies to the various doses discussed in detail herein.

[0053] Generally, the term "effective amount" about an activating agent refers to the amount of an activating agent that is enough to cause a specific biological condition, effect and / or reaction. The absolute amount of a specific agent that works in this way can vary according to various factors, such as expected biological endpoints, the agent itself, its subject or targeting moiety and / or similar factors. The activating agent of an effective amount can be administered in single doses or multiple doses. The examples of biological conditions, effects or reactions that the activating agent of an effective amount can produce include maintaining and / or improving the performance of a task related to cognitive function or cognitive function related to the subject, maintaining and / or improving the performance of a subject in a test measuring cognitive function or cognitive function related things, maintaining and / or improving (for example, slowing down) the rate of decline of cognitive function, and / or similar examples. Components can be described herein as having at least an effective amount or at least having an effective amount such as being relevant to a specific goal or purpose (such as any goal or purpose described herein).

[0054] Typically, the term "fasting state" refers to a subject's dietary state in which the patient consumes a standard meal and fasts for about 6 hours (h), 7h, 8h, 9h, 10h, 11h, 12h, 6 to 10h, 8 to 12h, or 6 to 16h prior to administration of the dosage form. The patient may fast for another about 4 hours after administration.

[0055] Typically, the term "fed state" refers to a subject's dietary state in which the patient consumes a standard meal, fasts for about 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 6 to 10 hours, 8 to 12 hours, or 6 to 16 hours, and eats again about 30 minutes before the dosage form is administered. The patient may fast for another about 4 hours after administration.

[0056] Generally, the term "fluctuation value" refers to the peak plasma concentration (C max ) and the lowest plasma concentration of the drug (C min) The difference. Without wishing to be bound by theory, the lower the fluctuation value, the higher the steady-state bioavailability of the surfactant can be indicated.

[0057] Generally, the term "fluctuation index" refers to the fluctuation value expressed as a percentage of C avg (C max - C min ), that is, ((C max - C min ) / C avg ) * 100%, where C avg refers to AUC / time interval.

[0058] Generally, the term "modified release" refers to a mechanism for delaying the delivery of a drug (delayed release dose) or releasing it over a longer period of time (extended release dose) or releasing it at a specific target site in the body (targeted release dose) after drug administration. Extended release includes sustained release and controlled release. Sustained release means maintaining drug release over a continuous period of time, but not at a constant rate, such as first-order release. Controlled release means maintaining drug release at an almost constant rate over a continuous period of time, such as zero-order release.

[0059] Generally, the term "pharmacokinetics" (PK) refers to the study of the fate of pharmaceutical products from the time they are taken up until they are eliminated from the body. The sequence of events for an oral composition can include absorption through various mucosal surfaces, distribution via the bloodstream to various tissues, biotransformation in the liver and other tissues, action at the target site, and elimination of the drug or metabolite in urine or bile.

[0060] Generally, the term "physiologically acceptable" or "pharmaceutically acceptable" means biologically or pharmacologically compatible for use in an animal or human body, for example, approved by a regulatory agency of the federal or state government or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, more particularly in humans.

[0061] Generally, the term "oral dose" or "oral dosage form" refers to any orally administered composition containing magnesium (Mg) and threonate (T) as active agents. In some cases, the oral dosage form includes a single type of oral dosage form (e.g., tablets, gels, etc.). Each of the single types of oral dosage forms may include one or more unit doses or include 1 to 10 unit doses (e.g., 1 to 10 tablets), 1 to 5 unit doses, or 1 to 3 unit doses. The unit dose may be in the form of tablets, pills, gels, capsules, soft gelatin capsules, or any other form 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 2 to 5 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.).

[0062] Generally, the term "systemic drug concentration" refers to the drug concentration in the body fluids of a mammal, such as blood or plasma, serum, urine, saliva, and / or other body fluids that are easily sampled. The term may also include the drug concentration in tissues that are systemically fluid-infiltrated, including the skin.

[0063] Generally, the term "skewness" refers to a characterization of the degree of asymmetry of the plasma concentration curve around the mean plasma concentration value.

[0064] Generally, 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 a subject or patient with a normal, good, or excellent health, emotional, cognitive, and / or nutritional status, or a subject or patient with an impaired health, emotional, cognitive, and / or nutritional status, including abnormal, weak, injured, unhealthy, damaged, diseased, and / or nutritionally deficient status. The subject may be of any age, including advanced age.

[0065] As used herein, the term "tablet" generally refers to tablets, cachets, capsules, including soft gelatin capsules, and lozenges.

[0066] As used herein, the term "treat" in all its verb forms includes alleviating or reducing at least one symptom of a disorder in a subject, the disorder including, for example, pain, Alzheimer's disease, vascular dementia or Parkinson's disease. The term "treat" can mean alleviating or reducing the intensity and / or duration of the manifestation of a disorder experienced by a patient in response to a given stimulus (e.g., stress, tissue injury, hypothermia, etc.). For example, with respect to dementia, the term "treat" can mean alleviating or reducing cognitive impairment (such as memory and / or orientation impairment) or overall functional impairment (activities of daily living, ADL) and / or slowing or reversing the progressive deterioration of ADL or cognitive ability. The term "treat" also means preventing, delaying the onset (i.e., the period prior to the clinical manifestation of the disease) and / or reducing the risk of disease development or worsening. The term "prevent" is used herein to mean preventing, delaying or treating (or all, as the case may be) the development, persistence or exacerbation of a 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 "treat" includes the "treatment" effects as defined above.

[0067] There is provided a dosage form containing magnesium (Mg) and threonate (T), formulated and / or administered to provide a serum or plasma concentration over an intended period of time that is high enough to be physiologically effective but not so high at any given time as to cause an adverse event or reduce the physiological effect.

[0068] The dose-response curve of magnesium threonate is bell-shaped ( Figure 8 ), such that efficacy decreases when the dose is increased beyond a certain point. The concentration range at which magnesium threonate reaches a therapeutic response is relatively narrow. This unique property of magnesium threonate suggests that for a given AUC, efficacy may be affected by the shape of the serum or plasma concentration curve. For a dosage form, sustained release of magnesium threonate can be used to reduce and delay peak plasma levels while maintaining a physiologically effective blood concentration. The sustained release formulation has lower fluctuations than immediate release dosage forms and zero-order controlled release dosage forms (Table 2), resulting in better efficacy (see, e.g., Figure 5). In addition, due to the delay in time to obtain peak serum or plasma levels and the extended period of time of therapeutically effective serum or plasma levels, the dosing frequency can be reduced to, for example, once or twice daily dosing, thereby improving subject compliance and adherence. Reducing concentration fluctuations also reduces the concentration of the active ingredient at its maximum time point and provides a more constant amount of magnesium threonate to the treated subject over a given period of time.

[0069] There is provided a dosage form comprising magnesium threonate for treating a disease, disorder, syndrome or condition in a patient in need thereof, wherein:

[0070] (a) At least a part of the magnesium (Mg) and threonate (T) in magnesium threonate exists in the form of a salt of MgT2;

[0071] (b) Magnesium threonate is present in an amount between about 200 and 6000 mg;

[0072] (c) When administered to a patient in need, the dosage form is sufficient to provide a certain in vivo plasma profile of threonic acid, and the in vivo plasma profile includes an average C between about 5 μg / mL and about 20 μg / mL avg .

[0073] There is also provided a dosage form comprising magnesium threonate, wherein:

[0074] (a) At least a part of the magnesium (Mg) and threonate (T) in magnesium threonate exists in the form of a salt of MgT2;

[0075] (b) Magnesium threonate is present in an amount between about 200 and 6000 mg; and

[0076] (c) The in vivo plasma profile from the dosage form exhibits a fluctuation index of less than about 170%.

[0077] There is also provided a dosage form comprising magnesium threonate, wherein:

[0078] (a) At least a part of the magnesium (Mg) and threonate (T) in magnesium threonate exists in the form of a salt of MgT2;

[0079] (b) Magnesium threonate is present in an amount between about 200 and 6000 mg; and

[0080] (c) The release of magnesium threonate from the dosage form exhibits a first-order release constant between about 0.2 h -1 and 0.6 h -1 and the first-order release constant is calculated from the measured values obtained using a USP II type (paddle) dissolution system at 75 rpm at a temperature of about 37 °C.

[0081] There is also provided a dosage form comprising magnesium threonate, wherein:

[0082] (a) At least a part of the magnesium (Mg) and threonate (T) in the magnesium threonate exists in the form of a salt of MgT2;

[0083] (b) The magnesium threonate is present in an amount between about 200 and 6000 mg; and

[0084] (c) The in vivo plasma profile from the dosage form exhibits a skewness of less than about 0.2.

[0085] There is also provided a dosage form comprising magnesium threonate, wherein:

[0086] (a) At least a portion of the magnesium (Mg) and threonate (T) of magnesium threonate is present in the form of the salt MgT2;

[0087] (b) Magnesium threonate is present in an amount of about 17.5 mg / kg LBM / dose; and

[0088] (c) When administered at a therapeutic dose to a patient in a fed state, the dosage form is sufficient to provide a certain in vivo plasma profile of threonic acid, which in vivo plasma profile includes:

[0089] (i) A 24-hour average AUC (AUC 0-24 ) of at least about 70 μg·h / mL; and

[0090] (ii) An average C max of less than about 13 μg / mL.

[0091] In some embodiments, the dosage form is formulated for oral administration. In some embodiments, the dosage form is sufficient to provide a certain in vivo plasma profile of threonic acid, which in vivo plasma profile includes an average T of at least about 4.5 hours max .

[0092] In some embodiments, the dosage form is liquid, semi-liquid, semi-solid or solid. In some embodiments, the dosage form is a gel, pill, tablet, capsule, bead, emulsion, granule, paste, pellet, powder, syrup, suspension, slurry or aerosol.

[0093] In some embodiments, the dosage form comprises at least 2 or more unit doses, for example, 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 different in vitro dissolution profiles in a dissolution medium. In some embodiments, the dosage form comprises three identical tablets, and the three identical tablets exhibit substantially the same in vitro dissolution profile in a dissolution medium. In some embodiments, the dosage form comprises a tablet and a capsule, and the tablet and the capsule exhibit different in vitro dissolution profiles in a dissolution medium. In some embodiments, the dosage form comprises two or more separate unit doses, wherein each unit dose exhibits substantially the same in vitro dissolution profile in a dissolution medium.

[0094] In some embodiments, the release of magnesium threonate from the dosage form exhibits a value between about 0.2 h -1 and 0.6 h -1The first-order release constant between them is calculated from the measured values obtained using a USP Type II (paddle) dissolution system at 75 rpm and a temperature of about 37°C. In some embodiments, the first-order release constant is between about 0.25 and 0.45, and is calculated from the measured values obtained using a USP Type II (paddle) dissolution system at 75 rpm and a temperature of about 37°C. In some embodiments, the first-order release constant is between about 0.3 h -1 and 0.4 h -1 between them, and is calculated from the measured values obtained using a USP Type II (paddle) dissolution system at 75 rpm and a temperature of about 37°C.

[0095] In some embodiments, the in vivo plasma profile from the dosage form exhibits a fluctuation index of less than about 170%. In some embodiments, the in vivo plasma profile from the dosage form exhibits a fluctuation index of less than about 165%. In some embodiments, the in vivo plasma profile from the dosage form exhibits a fluctuation index of less than about 160%. In some embodiments, the in vivo plasma profile from the dosage form exhibits a fluctuation index of less than about 155%.

[0096] In some embodiments, the in vivo plasma profile from the dosage form exhibits a skewness of less than about 0.2.

[0097] In some embodiments, the first-order release constant is between about 0.25 h -1 and 0.45 h -1 between them, and is calculated from the measured values obtained using a USP Type II (paddle) dissolution system at 75 rpm and a temperature of about 37°C, and the in vivo plasma profile from the dosage form exhibits a fluctuation index of less than about 170%. In some embodiments, the first-order release constant is between about 0.3 h -1 and 0.4 h -1 between them, and is calculated from the measured values obtained using a USP Type II (paddle) dissolution system at 75 rpm and a temperature of about 37°C, and the in vivo plasma profile from the dosage form exhibits a fluctuation index of less than about 170%.

[0098] In some embodiments, when administered to a patient in a fed state, the dosage form is sufficient to provide a certain threonic acid in vivo plasma profile, which includes an average fluctuation value of less than about 14 μg / mL. In some embodiments, the dosage form provides an average fluctuation value 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 lower (C max -C min ). In some embodiments, the fluctuation value (Cmax -C min ) ranges from 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, about 11 μg / mL to about 10 μg / mL. In some embodiments, the dosage form provides a particular threonic acid in vivo plasma profile that includes an average fluctuation value of less than about 10 μg / mL of magnesium threonate per gram of magnesium threonate administered. In some embodiments, when administered to a patient in a fed state, the dosage form is sufficient to provide a particular threonic acid in vivo plasma profile that includes an average fluctuation value of less than about 10 μg / mL of magnesium threonate per gram of magnesium threonate administered.

[0099] The model diagram shows that formula B administered theoretically once every 12 hours produces a lower fluctuation value (10.9) than that of formula A (14.2) ( Figure 3 ).

[0100] In some embodiments, the in vitro dissolution profile of the dosage form in the dissolution medium ranges from about 10% to 50% in about 1 hour. In some embodiments, the in vitro dissolution profile of the dosage form in the dissolution medium ranges from about 10% to 60% in about 2 hours. In some embodiments, the in vitro dissolution profile of the dosage form in the dissolution medium ranges from about 20% to 80% in about 4 hours. In some embodiments, the in vitro dissolution profile of the dosage form in the dissolution medium ranges from about 50% to 90% in about 6 hours. In some embodiments, measured using a USP type II (paddle) dissolution system at 75 rpm at a temperature of about 37 °C, the in vitro dissolution profile of the dosage form in the dissolution medium is as follows: (i) ranges from about 10% to 50% in about 1 hour; (ii) ranges from about 10% to 60% in about 2 hours; (iii) ranges from about 20% to 80% in about 4 hours; (iv) ranges from about 50% to 90% in about 6 hours; and (v) is greater than or equal to about 80% in about 8 hours.

[0101] In some embodiments, when administered to a patient in need, the dosage form is sufficient to provide a particular threonic acid in vivo plasma profile that includes an average C between about 5 μg / mL and about 20 μg / mL avg . In some embodiments, when administered to a patient in need, the dosage form is sufficient to provide a particular threonic acid in vivo plasma profile that includes an average C between about 5 μg / mL and about 15 μg / mL avg .

[0102] In some embodiments, the dosage form provides a certain plasma profile of threonic acid in vivo, and the plasma profile in vivo includes an average AUC of at least about 55 μg·h / mL based on a dose of 17.5 mg / kg LBM / dose. 0-24 In some embodiments, when administered to a patient in a fed state, the dosage form is sufficient to provide a certain plasma profile of threonic acid in vivo, and the plasma profile in vivo includes an average AUC of at least about 55 μg·h / mL based on a dose of 17.5 mg / kg LBM / dose. 0-24 In some embodiments, the dosage form is formulated such that when administered in vivo, it provides a certain plasma profile of threonic acid in vivo, and the plasma profile in vivo includes a 24-hour average AUC (AUC 0-24 ) of 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 higher. In some embodiments, the AUC 0-24 is from about 100 μg·h / mL to about 500 μg·h / mL, from about 100 μg·h / mL to about 200 μg·h / mL, or from about 103 μg·h / mL to about 120 μg·h / mL. In some embodiments, the percentage fluctuation between the AUC 0-24 measured under fed conditions and fasting conditions ((AUC 0-24 under fed - AUC 0-24 under fasting) / AUC 0-24 under fasting) is at least greater than 50%, 100%, 150% or more. In some embodiments, the absolute fluctuation between the AUC 0-24 measured under fed conditions and fasting conditions is at least about 20 μg·h / mL, 25 μg·h / mL, 30 μg·h / mL, 35 μg·h / mL or higher.

[0103] In some embodiments, the dosage form provides a certain plasma profile of threonic acid in vivo, and the plasma profile in vivo includes an average C of less than about 13 μg / mL based on a dose of 17.5 mg / kg LBM / dose. max In some embodiments, when administered to a patient in a fed state, the dosage form is sufficient to provide a certain plasma profile of threonic acid in vivo, and the plasma profile in vivo includes an average C of less than about 13 μg / mL based on a dose of 17.5 mg / kg LBM / dose. max .

[0104] In some embodiments, the dosage form provides a certain threonic acid in vivo plasma profile, the in vivo plasma profile including an average 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 a certain threonic acid in vivo plasma profile, the in vivo plasma profile including an average 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, about 16 μg / mL to about 12 μg / mL max .

[0105] In some embodiments, the dosage form provides a certain threonic acid in vivo plasma profile, the in vivo plasma profile including an average 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 longer max .

[0106] In some embodiments, it is administered once every 12 hours to a patient in need of treating a disease, disorder, syndrome, or condition, and the dosage form is sufficient to provide at least about 15 to 30 mg / kg lean body mass / dose of magnesium threonate (30 - 60 mg / kg LBM / day). In some embodiments, it is administered once every 12 hours to a patient in need of treating a disease, disorder, syndrome, or condition, and the dosage form is sufficient to provide at least about 15 mg / kg lean body mass / dose of magnesium threonate. In some embodiments, it is administered once every 24 hours to a patient in need of treating a disease, disorder, syndrome, or condition, and the dosage form is sufficient to provide at least about 15 mg / kg lean body mass / dose of magnesium threonate. In some embodiments, it is administered once every 24 hours to a patient in need of treating a disease, disorder, syndrome, and / or condition, and the dosage form is sufficient to provide about 10 to 30 mg / kg lean body mass / dose of magnesium threonate. In some embodiments, the dosage form is sufficient to provide at least about 30 mg / kg lean body mass / day of magnesium threonate. In some embodiments, the dosage form is sufficient to provide about 20 to 60 mg / kg lean body mass / day of magnesium threonate.

[0107] In some embodiments, the dosage form is sufficient to provide an amount of magnesium threonate from about 35 mg / kg LBM / day to about 50 mg / kg LBM / day. In some embodiments, the dosage form is sufficient to provide at least about 35 mg / kg LBM / day of magnesium threonate. In some embodiments, the dosage form is sufficient to provide at most about 50 mg / kg LBM / day of magnesium threonate. In some embodiments, the dosage form is sufficient to provide the following amounts of magnesium threonate: from about 35 mg / kg LBM / day to about 36 mg / kg LBM / day, from about 35 mg / kg LBM / day to about 37 mg / kg LBM / day, from about 35 mg / kg LBM / day to about 38 mg / kg LBM / day, from about 35 mg / kg LBM / day to about 39 mg / kg LBM / day, from about 35 mg / kg LBM / day to about 40 mg / kg LBM / day, from about 35 mg / kg LBM / day to about 42 mg / kg LBM / day, from about 35 mg / kg LBM / day to about 44 mg / kg LBM / day, from about 35 mg / kg LBM / day to about 46 mg / kg LBM / day, from about 35 mg / kg LBM / day to about 48 mg / kg LBM / day, from about 35 mg / kg LBM / day to about 50 mg / kg LBM / day, from about 36 mg / kg LBM / day to about 37 mg / kg LBM / day, from about 36 mg / kg LBM / day to about 38 mg / kg LBM / day, from about 36 mg / kg LBM / day to about 39 mg / kg LBM / day, from about 36 mg / kg LBM / day to about 40 mg / kg LBM / day, from about 36 mg / kg LBM / day to about 42 mg / kg LBM / day, from about 36 mg / kg LBM / day to about 44 mg / kg LBM / day, from about 36 mg / kg LBM / day to about 46 mg / kg LBM / day, from about 36 mg / kg LBM / day to about 48 mg / kg LBM / day, from about 36 mg / kg LBM / day to about 50 mg / kg LBM / day, from about 37 mg / kg LBM / day to about 38 mg / kg LBM / day, from about 37 mg / kg LBM / day to about 39 mg / kg LBM / day, from about 37 mg / kg LBM / day to about 40 mg / kg LBM / day, from about 37 mg / kg LBM / day to about 42 mg / kg LBM / day, from about 37 mg / kg LBM / day to about 44 mg / kg LBM / day, from about 37 mg / kg LBM / day to about 46 mg / kg LBM / day, from about 37 mg / kg LBM / day to about 48 mg / kg LBM / day, from about 37 mg / kg LBM / day to about 50 mg / kg LBM / day, from about 38 mg / kg LBM / day to about 39 mg / kg LBM / day, from about 38 mg / kgfrom about 38 mg / kg LBM / day to about 40 mg / kg LBM / day, from about 38 mg / kg LBM / day to about 42 mg / kg LBM / day, from about 38 mg / kg LBM / day to about 44 mg / kg LBM / day, from about 38 mg / kg LBM / day to about 46 mg / kg LBM / day, from about 38 mg / kg LBM / day to about 48 mg / kg LBM / day, from about 38 mg / kg LBM / day to about 50 mg / kg LBM / day, from about 39 mg / kg LBM / day to about 40 mg / kg LBM / day, from about 39 mg / kg LBM / day to about 42 mg / kg LBM / day, from about 39 mg / kg LBM / day to about 44 mg / kg LBM / day, from about 39 mg / kg LBM / day to about 46 mg / kg LBM / day, from about 39 mg / kg LBM / day to about 48 mg / kg LBM / day, from about 39 mg / kg LBM / day to about 50 mg / kg LBM / day, from about 40 mg / kg LBM / day to about 42 mg / kg LBM / day, from about 40 mg / kg LBM / day to about 44 mg / kg LBM / day, from about 40 mg / kg LBM / day to about 46 mg / kg LBM / day, from about 40 mg / kg LBM / day to about 48 mg / kg LBM / day, from about 40 mg / kg LBM / day to about 50 mg / kg LBM / day, from about 42 mg / kg LBM / day to about 44 mg / kg LBM / day, from about 42 mg / kg LBM / day to about 46 mg / kg LBM / day, from about 42 mg / kg LBM / day to about 48 mg / kg LBM / day, from about 42 mg / kg LBM / day to about 50 mg / kg LBM / day, from about 44 mg / kg LBM / day to about 46 mg / kg LBM / day, from about 44 mg / kg LBM / day to about 48 mg / kg LBM / day, from about 44 mg / kg LBM / day to about 50 mg / kg LBM / day, from about 46 mg / kg LBM / day to about 48 mg / kg LBM / day, from about 46 mg / kg LBM / day to about 50 mg / kg LBM / day, or from about 48 mg / kg LBM / day to about 50 mg / kg LBM / day. In some embodiments, the dosage form is sufficient to provide the following amounts of magnesium threonate: 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.

[0108] In some embodiments, the dosage form is sufficient to provide the following amount of magnesium threonate: 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 higher. In some embodiments, the dosage form is sufficient to provide the following amount of magnesium threonate: 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 lower.

[0109] In some embodiments, MgT2 is present in an amount of at least about 20 milligrams (mg) of magnesium (Mg) by weight. In some embodiments, magnesium (Mg) is present in an amount greater than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or more by weight. In some embodiments, magnesium (Mg) is present in an amount greater than about 1%, 5% or greater than about 7% by weight. In some embodiments, the average tablet specification of round tablets is about 10 mg to 150 mg of elemental Mg, while the average tablet specification of capsule-shaped tablets is about 20 mg to 200 mg of elemental Mg.

[0110] In some embodiments, the molar ratio of threonic acid (T) to magnesium (Mg) is greater than or equal to about 0.1:2.

[0111] In some embodiments, the dosage form comprises at least about 200 mg of magnesium threonate. In some embodiments, the dosage form comprises at most about 6,000 mg of magnesium threonate. In some embodiments, the dosage form comprises from about 200 mg to about 6,000 mg of magnesium threonate. In some embodiments, magnesium threonate is present in an amount between about 200 and 4000 mg. In some embodiments, the dosage form comprises the following amounts of magnesium threonate: about 200 mg to about 300 mg, about 200 mg to about 400 mg, about 200 mg to about 500 mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 200 mg to about 2,000 mg, about 200 mg to about 2,500 mg, about 200 mg to about 3,000 mg, about 200 mg to about 4,000 mg, about 200 mg to about 5,000 mg, about 200 mg to about 6,000 mg, about 300 mg to about 400 mg, about 300 mg to about 500 mg, about 300 mg to about 1,000 mg, about 300 mg to about 1,500 mg, about 300 mg to about 2,000 mg, about 300 mg to about 2,500 mg, about 300 mg to about 3,000 mg, about 300 mg to about 4,000 mg, about 300 mg to about 5,000 mg, about 300 mg to about 6,000 mg, about 400 mg to about 500 mg, about 400 mg to about 1,000 mg, about 400 mg to about 1,500 mg, about 400 mg to about 2,000 mg, about 400 mg to about 2,500 mg, about 400 mg to about 3,000 mg, about 400 mg to about 4,000 mg, about 400 mg to about 5,000 mg, about 400 mg to about 6,000 mg, about 500 mg to about 1,000 mg, about 500 mg to about 1,500 mg, about 500 mg to about 2,000 mg, about 500 mg to about 2,500 mg, about 500 mg to about 3,000 mg, about 500 mg to about 4,000 mg, about 500 mg to about 5,000 mg, about 500 mg to about 6,000 mg, about 1,000 mg to about 1,500 mg, about 1,000 mg to about 2,000 mg, about 1,000 mg to about 2,500 mg, about 1,000 mg to about 3,000 mg, about 1,000 mg to about 4,000 mg, about 1,000 mg to about 5,000 mg, about 1,000 mg to about 6,000 mg, about 1,500 mg to about 2,000 mg, about 1,500 mg to about 2,500 mg, about 1,500 mg to about 3,000 mg, about 1,500 mg to about 4,000 mg, about 1,500 mg to about 5,000 mg, about 1,500 mg to about 6,000 mg, about 2,000 mg to about 2,500 mg, about 2,000 mg to about 3,000 mg, about 2,000 mg to about 4,000 mg, about 2,000 mg to about 5,000 mg, about 2,000 mg to about 6,000 mg, about 2,500 mg to about 3,000 mg, about 2,500 mg to about 4,000 mg, 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 comprises the following amounts of magnesium threonate: 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.,

[0112] In some embodiments, magnesium threonate is present in the dosage form in an amount less than about 77.5% by weight. In some embodiments, magnesium threonate is present in an amount less than about 77% by weight. In some embodiments, magnesium threonate is present in an amount between about 40% and about 77% weight / weight. In some embodiments, magnesium threonate is present in an amount between about 45% and about 70% weight / weight. 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%.

[0113] In some embodiments, the dosage form further comprises carnauba wax as a binder. In some embodiments, carnauba wax is present in an amount between about 10% and about 30% weight / weight. In some embodiments, carnauba wax is present in an amount of about 28% weight / weight. In some embodiments, carnauba wax is present in an amount of about 10% weight / weight.

[0114] In some embodiments, the dosage form further comprises a lubricant. The lubricant comprises, for example, calcium stearate or magnesium stearate. In some embodiments, the dosage form further comprises magnesium stearate as a lubricant. In some embodiments, magnesium stearate is present in an amount between about 1% and about 3% weight / weight. In some embodiments, magnesium stearate is present in an amount between about 1% and about 2% weight / weight. In some embodiments, magnesium stearate is present in an amount of about 1.4% weight / weight. In some embodiments, magnesium stearate is present in an amount of about 2% weight / weight.

[0115] 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 greater. In some embodiments, the weight ratio of carnauba wax to magnesium stearate is about 20. In some embodiments, carnauba wax and magnesium stearate are combined and present in the dosage form in an amount of at least about 22.5% by weight.

[0116] 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 between about 4 and 8. In some embodiments, the weight ratio of carnauba wax to magnesium stearate is between about 4 and 6. In some embodiments, the weight ratio of carnauba wax to magnesium stearate is about 5.

[0117] In some embodiments, magnesium threonate is present in an amount 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% or less by weight. Alternatively or additionally, 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% or more by weight.

[0118] In some embodiments, magnesium threonate is present in an amount less than about 77% by weight, and the combination of carnauba wax and magnesium stearate is present in an amount less than about 15% by weight. In some embodiments, magnesium threonate is present in an amount less than about 60% by weight, and the combination of carnauba wax and magnesium stearate is present in an amount less than about 15% by weight. In some embodiments, magnesium threonate is present in an amount between about 40% and 60% by weight, and the combination of carnauba wax and magnesium stearate is present in an amount between about 10% and 15% by weight. In some embodiments, magnesium threonate is present in an amount between about 50% and 55% by weight, and the combination of carnauba wax and magnesium stearate is present in an amount between about 10% and 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.

[0119] In some embodiments, the dosage form comprises additional reagents.

[0120] In some embodiments, the additional reagent is a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable carrier is selected from the group consisting of micelles, liposomes, microspheres, nanofibers, and any combination thereof.

[0121] In some embodiments, the additional reagent is a pharmaceutically acceptable excipient. The compositions described herein comprise one excipient or any combination of excipients such as, but not limited to, diluents, binders, disintegrants, glidants, lubricants, colorants, flavorants, solvents, film-forming polymers, plasticizers, opacifying agents, anti-adherent agents, and polishing agents. In some embodiments, the pharmaceutically acceptable excipients are selected from the group consisting of binders, fillers, lubricants, dissolution aids, and any combination thereof. In some embodiments, the pharmaceutically acceptable excipients are selected from the group consisting of: lactose, microcrystalline cellulose, silica, titanium dioxide, stearic acid, starch, sodium starch glycolate, polyvinylpyrrolidone, pregelatinized starch, cross-linked carboxymethylcellulose, ethylcellulose, dicalcium phosphate, talc, sucrose, calcium stearate, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, hydrogenated vegetable oil, beeswax, and any combination thereof.

[0122] In some embodiments, the compositions described herein are formulated using any of the following excipients or combinations thereof.

[0123] Table 1

[0124]

[0125]

[0126] In some embodiments, the magnesium compositions described herein include a carrier (such as a solvent), a dispersion medium, a coating material, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents. The use of such media and reagents for pharmaceutically active substances is well known in the art. Acceptable salts can also be used in the compositions, such as inorganic salts, such as hydrochloride, hydrobromide, phosphate, or sulfate salts, and organic acid salts, such as acetate, propionate, malonate, or benzoate salts. In some embodiments, the composition also contains 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. Patent No. 5,422,120, PCT Application WO 95 / 13796, or WO 91 / 14445, or European Patent EP524,968B1, can also be used as carriers.

[0127] In some embodiments, another material is added to magnesium threonate as a compressibility enhancer. Such additional materials include silica, non-silicon metal oxides, starches, starch derivatives, surfactants, polyalkylene oxides, cellulose A ethers, cellulose esters, mixtures thereof, and the like. Other specific materials that can be included in the aqueous slurry (and thus can be included in the resulting coalesced microcrystalline cellulose excipient) include alumina, 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, and the like. These additives can be included in the desired amounts, which will be apparent to those skilled in the art.

[0128] In addition to one or more active ingredients, other additives known to those skilled in the art can be added to the novel excipient before the final product is prepared. For example, if desired, any commonly accepted soluble or insoluble inert filler (diluent) material can be included in the final product (e.g., solid dosage form). In some embodiments, such inert fillers include monosaccharides, disaccharides, polyols, inorganic phosphates, sulfates or carbonates, and / or mixtures thereof. Examples of suitable inert fillers include sucrose, dextrose, lactose, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, calcium carbonate, microcrystalline cellulose, mixtures thereof, and the like.

[0129] In some embodiments, the composition comprises an excipient that can swell and expand in amount, and the excipient is a swellable material, such as a hydrogel. Examples of swellable materials include lightly crosslinked hydrophilic polymers, such crosslinking being formed by covalent or ionic bonds, and these hydrophilic polymers interact with water and aqueous biological fluids and swell or expand to a certain equilibrium state. Swellable materials such as hydrogels exhibit the ability to swell in water and retain a large portion of water within their structure, and they do not dissolve in water when crosslinked. The swellable polymer can swell or expand to a high degree, showing a volume increase of 2 to 50 times. Specific examples of hydrophilic polymer materials include poly(hydroxyalkyl methacrylate), poly(N-vinyl-2-pyrrolidone), anionic and cationic hydrogels, polyelectrolyte complexes, poly(vinyl alcohol) with low acetate residue and crosslinked with glyoxal, formaldehyde or glutaraldehyde, methylcellulose crosslinked with dialdehyde, a mixture of crosslinked agar and carboxymethylcellulose, a water-insoluble water-swellable copolymer prepared by forming a dispersion of a segmented copolymer of maleic anhydride with styrene, ethylene, propylene, butene or isobutene (crosslinked with 0.001 to about 0.5 moles of polyunsaturated crosslinker per mole of maleic anhydride in the copolymer), a water-swellable polymer of N-vinyl lactam, crosslinked polyethylene oxide, etc. Other examples of swellable materials include hydrogels showing a degree of crosslinking of 0.05% to 60%, called Carbopol. TM Hydrophilic hydrogel of acidic carboxyl polymer, Cyanamer. TM Polyacrylamide, crosslinked water-swellable indene-maleic anhydride polymer, Good-rite. TM Polyacrylic acid, polyethylene oxide, starch graft copolymer, Aqua-Keeps. TM Acrylate polymer, dextran crosslinked with diester, etc. Methods for testing swellable materials regarding polymer imbibition pressure and hydrogel-water interface interaction are described in U.S. Patent No. 4,327,725, titled "Osmotic device with hydrogel driving member", issued on May 4, 1982.

[0130] In some embodiments, the dosage forms described herein also contain an effective amount of a colorant (such as titanium dioxide, F.D.&C. and D.&C. dyes; see Kirk-Othmer Encyclopedia of Chemical Technology, Volume 5, pages 857 - 884, which is hereby incorporated by reference), stabilizers, binders, odor control agents, and preservatives.

[0131] In some embodiments, the additional reagent is a nutraceutical agent. In some embodiments, the nutraceutical agent is selected from the group consisting of calcium-containing materials, herbs, spices, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, niacin, folic acid, biotin, minerals, and any combination thereof. In some embodiments, the additional reagent is a threonate precursor.

[0132] Examples of immediate-release tablets (Formulation A) are shown in Example 1. The tablets of Formulation A contain magnesium L-threonate (450 mg) as the magnesium composition, carnauba wax as the binder, magnesium stearate as the lubricant, and a coating material that contains talc as the inert powder and hydrogenated vegetable oil. The weight ratio of carnauba wax to magnesium stearate is 12.

[0133] Examples of sustained-release tablets (Formulation B) are shown in Example 2. The tablets of Formulation B contain magnesium L-threonate (500 mg) as the magnesium composition, carnauba wax as the binder, magnesium stearate as the lubricant, and a coating material that contains talc as the inert powder and hydrogenated vegetable oil. The weight ratio of carnauba wax to magnesium stearate is 20. Figure 1A , Figure 1B and Figure 1C In and are shown the in vitro dissolution profiles of Formulation B at pH 1.1 (designated as 114), 4.5 (designated as 124), and 6.8 (designated as 144). For Formulation B, the release profile of threonic acid may be substantially the same as the release profile of magnesium, measured at pH 1.1, 4.5, and 6.8 using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of about 37 °C, and ranges from: (i) between about 10% and 50% in about 1 hour; (ii) between about 10% and 60% in about 2 hours; (iii) between about 20% and 80% in about 4 hours; (iv) between about 50% and 90% in about 6 hours; and (v) greater than or equal to about 95% in about 8 hours.

[0134] Another example of a controlled-release tablet (Formulation C) is shown in Example 3. The tablets of Formulation C contain magnesium L-threonate (450 mg or 500 mg) as the magnesium composition, polyvinylpyrrolidone K-90 as the binder, microcrystalline cellulose as the glidant, colloidal silicon dioxide as the filler, carbopol and carboxymethyl cellulose as the swellable materials, Starcap starch, magnesium stearate lubricant, and talc as the inert powder. Figure 1A , Figure 1B and Figure 1DIn vitro dissolution curves of Formulation C at pH 1.1 (designated as 116) and 4.5 (designated as 126) are shown. For Formulation C, the release curve of threonic acid may be substantially the same as the release curve of magnesium, measured at pH 1.1 and 4.5 using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of about 37 °C, and it ranges as follows: (i) between about 10% and 30% in about 1 hour; (ii) between about 20% and 50% in about 2 hours; (iii) between about 40% and 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.

[0135] Another example of a dosage form is shown in Example 7. The tablets of Formulation D contain an inner granule portion and an outer granule portion. Figure 6 In vitro dissolution curves of Formulation D are shown.

[0136] In vivo plasma concentration curves of dosage forms (Formulation A, Formulation B, and Formulation C) containing magnesium threonate are shown in Example 4. In the experiment, human subjects received three tablets of any one of Formulation A, Formulation B, and Formulation C, for a total intake of about 1350 to 1500 mg of L-magnesium threonate. Some subjects fasted for at least 10 hours before oral administration of the tablets (fasting state). Some subjects ate a high-fat, high-calorie breakfast within 30 minutes before oral administration of the tablets ("fed state"). Blood samples were collected before dosing (baseline) and at multiple time intervals until 24 hours after dosing. Figure 2A - Figure 2F The resulting in vivo plasma concentration curves are shown. In the fasting state, relative to Formulation B (66.8 μg·h / mL) and Formulation A (79.2 μg·h / mL), oral administration of Formulation C exhibited the highest average AUC 0-24 (82.3 μg·h / mL)( Figure 2A ). In the fed state, relative to Formulation B (103.3 μg·h / mL) and Formulation A (98.2 μg·h / mL), oral administration of Formulation C exhibited the highest average AUC 0-24 (112.1 μg·h / mL)( Figure 2B ). For all three dosage forms (Formulation A, Formulation B, and Formulation C), administration of these dosage forms when the subjects were in the fed state produced higher average AUCs than when the subjects were in the fasting state 0-24 ( Figure 2C - Figure 2E ). In the fed state, relative to Formulation A or Formulation C, administration of Formulation B produced the lowest average C max (16.1 μg·h / mL) and the highest average T max (5.3 h) (Table 2). In the fed state, the in vivo plasma concentration curve of Formulation B produced a lower skewness value than Formulation AFigure 2F ). Without wishing to be bound by theory, the lower skewness of the in vivo plasma concentration curve of Formulation B may indicate that the active ingredient (magnesium L-threonate) is released into the circulation more slowly relative to Formulation A.

[0137] There is also provided a method of treating a disease, disorder, syndrome or condition in a patient in need thereof, the method comprising orally administering a dosage form as described herein.

[0138] In some embodiments, the dosage form comprising magnesium threonate is administered twice daily. In some embodiments, the dosage form is administered more than twice daily. The dosage form is administered three or more times daily. In some embodiments, the dosage form is administered at 12-hour intervals.

[0139] 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 longer. In some embodiments, the administration of the dosage form is repeated once a week, twice a week, three times a week, four times a week, five times a week, six times a week or seven times a week. In some embodiments, the 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, the 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, the administration of the dosage form is repeated continuously throughout life.

[0140] In some embodiments, the dosage form is administered twice daily with food. In some embodiments, the dosage form is administered to a patient in a fed state. In some embodiments, the method further comprises fasting the patient for at least about 4 hours after oral administration of the dosage form. In some embodiments, the dosage form is administered with food every 12 hours. In some embodiments, the patient eats a meal from about 0.5 h to about 4 h before administration of the dosage form. In some embodiments, the patient eats a meal at least about 0.5 h before administration of the dosage form. In some embodiments, the patient eats a meal at most about 4 h before administration of the dosage form. In some embodiments, the patient eats a meal from 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 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 before administration of the dosage form. In some embodiments, the patient eats 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.

[0141] In some embodiments, the patient has a disease, disorder, syndrome or condition selected from: cardiovascular disease, neurodegenerative disorder, sleep disorder, neurological disorder, nerve injury, developmental disorder / autism spectrum disorder, autoimmune disease, genetic disease, rheumatic disease, inflammatory disease and physical trauma.

[0142] In some embodiments, the patient has 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 disorder, stress, anxiety disorder, depression, sleep disorder, psychosis, metabolic disorder, fatigue, cancer, HIV, hepatitis, spinal cord injury, postoperative recovery, post-traumatic stress disorder, arthritis, neuropathic pain, inflammation, tremor, and fibromyalgia. In some embodiments, the patient has cognitive decline that is a secondary effect of a disease or medical condition (HIV disease, cancer, chemotherapy). Magnesium supplements can also be used to maintain, enhance, and / or improve conditions that can cause body magnesium loss, including but not limited to alcoholism, anorexia, bulimia, metabolic syndrome, and malnutrition.

[0143] In some embodiments, the patient is an adult.

[0144] In some embodiments, the method further comprises determining the physiological concentration of threonic acid in the patient prior to orally administering a dosage form comprising magnesium threonate. In some embodiments, the method further comprises determining at least one other physiological concentration of threonic acid in the patient after orally administering the dosage form. In some embodiments, the physiological concentration is a serum concentration, plasma concentration, urine concentration, or cerebrospinal fluid concentration. In some embodiments, the at least one other physiological concentration of threonic acid and / or magnesium is determined 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.

[0145] When administered in vivo, dosage form B disclosed herein exhibits superior physiological effects compared to a rapid-release dose of magnesium threonate (dosage form A). Such improved physiological effects include, but are not limited to, mood improvement and cognitive function, such as working memory, processing speed, and cognitive flexibility (see Figure 5).

[0146] Figure 4Examples of the effects of dosing by a subject's TBW and LBM are shown. In two experiments, male and female subjects received 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 (1) approximately 1.5 g of magnesium L-threonate per day (1.5 g / day) for subjects with a TBW between 50 and 70 kg, and (2) approximately 2 g of magnesium L-threonate per day (2 g / day) for subjects with a TBW between 70 and 100 kg. Male and female subjects between 50 - 70 years of age were administered magnesium L-threonate for 12 weeks. After administration of magnesium L-threonate, the efficacy in improving overall cognitive ability was determined by changes in performance on a neuropsychological test battery (NTB), which consists 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 combined standardized scores (z-scores) from individual cognitive tests for a clinical test population. In the second experiment, male and female schizophrenia patients between 18 - 55 years of age received 2 g of magnesium L-threonate per day (2 g / day). After 9 weeks of administration of magnesium L-threonate, the efficacy in improving overall cognitive ability was determined by changes in performance on the MATRICS Consensus Cognitive Battery (MCCB). The MCCB can also be expressed as a z-score. To evaluate the overall effect of magnesium L-threonate in the two studies, the data from the two studies were combined using the change in z-value relative to baseline. Subjects were divided into a high-dose group and a low-dose group, which were defined based on the median dose / day for all subjects in the two studies by TBW and LBM. 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 classifying subject scores by high and low doses by TBW, subjects receiving the high-dose drug (greater than 24 mg / kg TBW / day) did not perform better than subjects receiving the low-dose drug (less than 24 mg / kg TBW / day) ( Figure 4 , Chart 410). Alternatively, when classifying subject scores by high and low doses by LBM, subjects receiving the high-dose drug (greater than 35 mg / kg LBM / day) showed significantly greater improvement in overall cognitive ability than subjects receiving the low-dose drug (less than 35 mg / kg LBM / day) ( Figure 4 , Chart 420). Without wishing to be bound by theory, an estimated dose of magnesium L-threonate of about 35 mg / kg LBM / day for one or more days may be the minimum therapeutic dose for improving cognitive ability.

[0147] Examples of the differences in efficacy between different dosage forms are shown in Figure 5. As Figure 5AAs shown, subjects treated with a sustained-release dosage form with a lower fluctuation index (Formulation B) showed significantly better mood z-scores (higher mood scores indicate better mood) than subjects treated with an immediate-release dosage form (Formulation A) or placebo. Additionally, as Figure 5B and Figure 5C shown, only subjects treated with the sustained-release dosage form (Formulation B) showed significantly higher composite z-scores and backward span z-scores than subjects treated with placebo. Without wishing to be bound by theory, dosage forms with a certain fluctuation index can effectively improve cognitive ability.

[0148] Also provided is a method for preparing a dosage form comprising magnesium threonate. In some embodiments, the method for preparing the dosage form comprises forming a mixture comprising magnesium threonate and additional reagents. In some embodiments, the method for preparing the dosage form further comprises formulating the mixture to form the dosage form. In some embodiments, the dosage form comprises an amount of magnesium threonate between about 400 and 2000 mg.

[0149] Tablets are prepared by methods known in the art and, in some embodiments, further comprise suitable binders, fillers, lubricants, diluents, disintegrants (dissolution aids), colorants, flavorants, flow-inducing agents, melting agents, many of which are known in the art. In some embodiments, the dosage form has a film coating to protect the components of the magnesium counterion supplement composition from one or more of moisture, oxygen, and light, or to mask any undesirable taste or appearance. Suitable coating agents include, for example, cellulose, hydroxypropyl methylcellulose, crosslinked carboxymethylcellulose, and ethylcellulose. In some embodiments, the dosage form comprises a plurality of beads encapsulated in a capsule. Such forms can be used as extended-release formulations. Other forms of tablets can also be formulated as extended-release forms. Methods for preparing extended-release tablets (including controlled-release and sustained-release tablets) are known in the art, for example, see U.S. Patent Publication Nos. 2006 / 051416 and 2007 / 0065512, or other references disclosed herein.

[0150] In some embodiments, the dosage form is made by mixing a powder comprising magnesium (Mg) and threonate (T), both of which may be in the form of salts, with a polymer in an amount sufficient to produce particles comprising magnesium (Mg), threonic acid (T), and the polymer, wherein the particles are sized to be retained on a 12-mesh sieve. In some embodiments, the method further comprises: filtering the particles using a 12-mesh sieve to remove unbound threonate salts; drying the particles; adding an acceptable amount of lubricant to the particles; compressing the particles into one or more pills having a total size between about 100 mg and about 2000 mg, and coating the one or more pills with a polymer coating material comprising one or more of polyvinylpyrrolidone, polyvinyl acetate, and propylene glycol. In some embodiments, the elemental magnesium content of the prepared pills is from about 10 mg to about 200 mg.

[0151] In some embodiments, the dosage form comprises a plurality of beads, wherein each bead comprises a core having a diameter of from about 1 micrometer (μm) to about 1000 μm, and the core comprises an active ingredient comprising magnesium or a salt thereof in an amount ranging from about 15 to about 350 milligrams (mg) of magnesium (Mg) per gram (g) of dosage form, wherein the dosage form comprises less than about 2.5% adducts, and has a dissolution rate of greater than about 80% of the active ingredient within about the first 60 minutes after the dosage form enters the use environment. In some embodiments, the dissolution rate is greater than about 80% within 30 minutes.

[0152] 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, which are admixed with soluble components such as sugars (e.g., sucrose, mannitol, etc.), polymers (e.g., polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc.), surfactants (sodium dodecyl sulfate, chremophor, tween, span, pluronic, etc.), insoluble glidant components (microcrystalline cellulose, calcium phosphate, talc, calcined silica, etc.), coating materials (examples of suitable coating materials are polyethylene glycol, hydroxypropyl methyl cellulose, waxes, fatty acids, etc.), dispersions in suitable materials (examples are waxes, polymers, physiologically acceptable oils, soluble reagents, etc.) or combinations thereof.

[0153] According to some embodiments, the core comprises nonpareil seeds, microcrystalline cellulose or mannitol. In some embodiments, the core is a USP grade nonpareil seed (Paulaur Cranbury, N.J.). In some embodiments, the particle size of the core ranges from about 1 μm to about 1000 μm. In some embodiments, the particle size of the core ranges from about 300 μm to about 900 μm. In some embodiments, the particle size of the core ranges from about 450 μm to about 825 μm. In some embodiments, the core is coated to avoid interaction between the core and the active ingredient. For example, suitable coating materials include but are not limited to polyethylene glycol, hydroxypropyl methylcellulose, wax, fatty acids, etc.

[0154] In some embodiments, the spheres form part of the dosage form and range 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). The fraction of the beads will depend on the amount of additional components (if any) used in the dosage form.

[0155] The core can be coated with magnesium such as magnesium threonate. In some embodiments, 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 beads. In other embodiments, magnesium is present in an amount of about 15 to 300 mg / g, such as about 25 to about 250 mg / g.

[0156] In some embodiments, magnesium threonate is added to a 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 calcined silica. The glidant can be used in an amount in the range of 1.5 mg / g to about 35 mg / g. In some embodiments, the glidant ranges from about 1.5 mg / g to about 30 mg / g. In some embodiments, the glidant ranges from about 2.5 mg / g to about 25 mg / g. In some embodiments, the glidant ranges from about 5 mg / g to about 30 mg / g.

[0157] In some embodiments, the binder is selected from, but not limited to, polyvinylpyrrolidone (PVP), cross-linked carboxymethyl cellulose, ethyl cellulose, 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 in the range of 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 polyvinylpyrrolidone, the binder is present in an amount of from about 1.5 mg / g to about 35 mg / g, such as from about 5 mg / g to about 30 mg / g.

[0158] The mixture of the active ingredient and the binder / water / glidant can be prepared, for example, by mixing with a stirrer for at least 15 minutes, at least 30 minutes, or at least one hour. The components can also be combined by methods including blending, mixing, dissolving, and evaporation, or by using suspensions.

[0159] In some embodiments, the active ingredient / binder / inactive ingredient mixture is deposited on the core and wet agglomerated, extruded, granulated, or spray dried. In some embodiments, the sugar spheres are preheated to a temperature in the range of from about 40 °C to about 55 °C before applying the mixture. In some embodiments, the core is coated with a sealing coating material of from about 2% weight / weight (w / w) to about 10% w / w before applying the active layer. In some embodiments, the sealing coating material is any suitable coating material that can separate any active ingredient from the core, such as a polymer coating material, such as HPMC, HPC, or combinations thereof.

[0160] In some embodiments, the sugar spheres are coated using a fluid bed coater known in the art, such as a Glatt Powder Coater Granulator GPCG3 (Ramsey, N.Y.). Familiar coating conditions such as air flow rate, spray rate, and atomization pressure are generally controlled as recognized and known by those skilled in the art. In some embodiments, the temperature range is from about 43 °C to about 51 °C. In some embodiments, the air flow rate ranges from about 5 meters per second to about 9 meters per second (m / s). The spray rate ranges from about 9 to about 42 grams per minute (g / min). The atomization pressure can range from about 1.5 to about 2.0 bar. The beads are then dried in the fluid bed of the coating apparatus at a temperature of from 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 various types of equipment can also be used.

[0161] Once the beads are formed to contain a core of magnesium threonate as provided herein, the beads can optionally be further coated with a sealing coating material. In some embodiments, the sealing coating material is a polymer or a combination of polymers that can be designed to be pH-dependent or pH-independent. In some embodiments, the polymers used for the sealing coating material are selected from, but not limited to, HPMC( Colorcon, Pa.), HPC, RL, E100, E 12.5, E PO, NE (e.g., NE 30D or NE 40D) and combinations of two or more of the foregoing. These polymers are insoluble in aqueous media but exhibit pH-independent swelling when in contact with aqueous fluids. In some embodiments, the beads are coated with a pH-dependent polymer that is soluble at a pH such as above 5. In immediate-release bead formulations, the sealing coating polymer is present in an amount in the range of from about 0% w / w to about 40% w / w, such as from about 0% w / w to about 10% w / w, for example from about 0% w / w to about 3% w / w.

[0162] Alternatively, for aesthetic, handling, or stability purposes, the core is coated with a rapidly disintegrating or dissolving coating material. Suitable materials are polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, polymethacrylate containing free amino groups, each of which may or may not have a plasticizer, and may or may not have an anti-adhesive or filler. It is generally considered that a coating material that adds about 3% to the weight of the core can provide a continuous coating for this size range. In some embodiments, the outer coating material is a polymer selected from, but not limited to, the following: HPMC( Colorcon, Pa.), HPC, RL, E100, E 12.5, E PO, NE and mixtures thereof.

[0163] In some embodiments, the beads or bead mixtures are used, for example, as a suspension, filled into capsules, compressed into tablets, or filled into sachets. One or more types of extended-release beads can be mixed together and encapsulated, or sprinkled on the subject's food for use. 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, a encapsulating machine is used to formulate the beads into capsules. Various capsule sizes may be required to accommodate the strength and fill weight of the target formulation. For fill weights ranging from about 15 mg to about 630 mg, the capsule size ranges from 00 to 5.

[0164] The particle size of the immediate-release and extended-release bead components in the dosage form depends on the technology used to prepare them. The particle size range of the components is sub-micron to 500 μm for powder technologies (mixtures, spray drying, dispersions, etc.), 5 to 1700 μm for coating technologies ( top spray, bottom spray, spray drying, extrusion, layering, etc.), and 1 - 40 millimeters (mm) for tableting technologies.

[0165] In addition to the active ingredient comprising magnesium and threonate, the dosage form may also contain many physiologically acceptable excipients, which depends in part on the extended-release mechanism to be used. "Physiologically acceptable" includes molecular entities and compositions that do not produce adverse reactions, allergic reactions, or other untoward reactions when administered, as appropriate, to animals or humans, such as those that are pharmaceutically acceptable. "Physiologically acceptable carriers" include micelles, liposomes, microspheres, nanofibers, and any combination thereof. Physiologically acceptable carriers include any and all solvents, dispersion media, coating materials, antibacterial and antifungal agents, isotonic agents, and absorption delaying agents, etc. The use of such media and agents for physiologically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, it is contemplated for use in the magnesium threonate composition. Supplementary active ingredients may also be incorporated into the composition. "Physiologically acceptable salts" include acid addition salts and are formed with inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid, etc. Salts formed with free carboxyl groups may also be derived from inorganic bases (such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide) and organic bases (such as isopropylamine, trimethylamine, histidine, procaine, etc.). General techniques for formulation and administration are found in "Remington: The Science and Practice of Pharmacy, Twentieth Edition," published by Lippincott Williams & Wilkins, Philadelphia, Pa. Tablets, capsules, pills, powders, granules, dragees, gels, slurries, ointments, solution suppositories, injections, inhalants, and aerosols are examples of such formulations.

[0166] For example, other methods known in the art can be used to prepare extended-release oral formulations. For example, in some embodiments, suitable extended-release forms of the magnesium threonate compositions provided herein are matrix tablets or capsule compositions. Suitable matrix-forming materials include, for example, waxes (e.g., carnauba wax, beeswax, paraffin wax, ozokerite, shellac wax, fatty acids and fatty alcohols), oils (e.g., hydrogenated vegetable oils), hardened oils or fats (e.g., hardened rapeseed oil, castor oil, tallow, palm oil and soybean oil), and polymers (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose and polyethylene glycol). Other suitable matrix tableting materials are microcrystalline cellulose, powdered cellulose, hydroxypropyl cellulose, ethyl cellulose, and other carriers and fillers. In some embodiments, the tablets contain granules, coating powders or pellets. In some embodiments, the tablets are multilayered. Multilayer tablets are useful when the active ingredients (e.g., different forms of magnesium and threonate) have significantly different pharmacokinetic profiles. Optionally, the finished tablets are coated or uncoated.

[0167] The coating composition generally contains an insoluble matrix polymer (about 15% - 85% by weight of the coating composition) and a water-soluble material (e.g., about 15% - 85% by weight of the coating composition). Optionally, an enteric polymer (about 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, phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, shellac, zein, and carboxyl-containing polymethacrylates.

[0168] In some embodiments, the coating composition is plasticized according to the nature of the coating blend, such as the glass transition temperature of the main component or components of the coating composition mixture or solvent used to apply the coating composition. A suitable plasticizer can be added in an amount of 0% to 50% by weight of the coating composition and includes, for example, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerol esters, acetylated citrate esters, dibutyl sebacate, and castor oil. If desired, the coating composition can contain a filler. Based on the total weight of the coating composition, the amount of the filler by weight can be 1% to about 99%, and can be an insoluble material such as silica, titanium dioxide, talc, kaolin, alumina, starch, powdered cellulose, magnesium-containing compounds, or polacrilin potassium.

[0169] The coating composition can be applied as a solution or a latex in an organic solvent or an aqueous solvent or a mixture thereof. If a solution is applied, the solvent is present in an amount of about 25% - 99% by weight, based on the total weight of the dissolved solids. Suitable solvents are water, lower alcohols, lower chlorinated hydrocarbons, ketones or mixtures thereof. If a latex is applied, the solvent is present in an amount of about 25% - 97% by weight, based on the amount of polymeric material in the latex. The solvent can be mainly water.

[0170] In some embodiments utilizing a spray drying method, an aqueous dispersion of magnesium threonate and a compressibility enhancer (e.g., a surfactant or silica) is mixed with a sufficient volume of hot air to cause evaporation and drying of the droplets. The highly dispersed slurry is pumpable and capable of being atomized. It is sprayed into a warm stream of filtered air, which provides heat for evaporation and conveys the dried product to a collection device. Then, the air is exhausted along with the expelled moisture. The resulting spray-dried powder particles can be approximately spherical in shape and relatively uniform in size, thus having excellent flowability. The co-processed particles are not necessarily uniform or homogeneous. Other drying techniques can also be used, such as flash drying, ring drying, micron drying, tray drying, vacuum drying, radio frequency drying, and possibly microwave drying.

[0171] Alternatively, all or part of the excipients can be wet granulated together with the active ingredient. Representative wet granulation includes loading novel excipient particles into a suitable granulator, such as those available from Baker-Perkins, and granulating the particles together with the active ingredient, for example, using an aqueous granulating liquid. In some embodiments, a portion of the total amount of the novel excipient is wet granulated with the active ingredient, and then another portion of the novel excipient is added to the granules. In other embodiments, another portion of the novel excipient to be added to the excipient / active ingredient granules can be replaced with other excipients commonly used by those skilled in the art, depending, of course, on the requirements of the particular formulation.

[0172] Then, an amount of the complete mixture sufficient to prepare a uniform batch of tablets can be tabletted in a conventional production-scale tablet press at the normal compression pressure of the tablet press, for example, about 1500 - 10,000 pounds per square inch (lbs / sq in). The mixture should not be compressed to an extent that subsequent difficulties exist in its hydration when exposed to gastric juice.

[0173] In some embodiments, the compositions described herein are prepared using the formulations described in U.S. Patent 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.

[0174] In addition to oral dosage forms, the compositions 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, intra-arterial, or intradermal modes of administration, in the form of dosage unit formulations (such as depot or controlled-release formulations) containing conventional non-toxic, physiologically acceptable carriers, adjuvants, and the required vehicles. Depending on the route of administration, the compositions can be formulated as suppositories, lotions, patches, or devices (e.g., a subcutaneously implantable delivery device or an inhalation pump). The compositions can be optimized for a particular type of delivery.

[0175] In some embodiments, magnesium threonate is delivered in the form of an aerosol spray formulation from a pressurized pack, a nebulizer, or from a dry powder inhaler. Suitable propellants that can be used in a nebulizer include, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, and carbon dioxide. In the case of a pressurized aerosol, the dose can be determined by providing a valve to deliver a regulated amount of the compound.

[0176] Compositions for inhalation or insufflation include solutions and suspensions, as well as powders, in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid compositions can contain suitable excipients as described above. The compositions in acceptable solvents can be atomized by using an inert gas. The atomized solution can be breathed directly from the atomizing device, or the atomizing device can be connected to a face mask, a nasal plug, or an intermittent positive pressure ventilator. The solution, suspension, or powder composition can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0177] In some embodiments, the compositions can be administered transdermally, as generally described, for example, in U.S. Patent Nos. 5,186,938, 6,183,770, 4,861,800, 6,743,211, 6,945,952, 4,284,444, and WO 89 / 09051.

[0178] In some embodiments, the compositions can be delivered to the brain by intranasal, buccal, or sublingual routes, rather than by inhalation, enabling the active agent to transfer to the CNS through the olfactory pathway and reducing systemic administration. U.S. Patent No. 6,715,485 includes devices commonly used for this route of administration.

[0179] Methods known in the art, such as those described in, for example, U.S. Patent Nos. 3,992,518, 5,660,848, 5,756,115, 5,422,123, 5,601,845, 5,912,013, and 6,194,000, can be used for the preparation of compositions for delivery in a subcutaneously implantable device.

[0180] Examples

[0181] Example 1

[0182] Preparation and dissolution profiles of immediate-release tablets.

[0183] Examples of immediate-release tablets (Formulation A) are discussed. Tablets of Formulation A contain magnesium L-threonate (450 mg) as a magnesium composition, carnauba wax as a binder, magnesium stearate as a lubricant, and a moisture barrier coating. The weight ratio of carnauba wax to magnesium stearate is 12.

[0184] Ingredient Mg / tablet %, weight / weight Magnesium threonate 450 77.58 Carnauba wax 120 20.69 Magnesium stearate, NF 10 1.72 Total amount 580.00 100.00

[0185] In a USP Type II (paddle) dissolution system, the release profiles of the tablets of Formulation A prepared above were examined at 75 rpm at a temperature of about 37 °C in 0.1 N HCl (pH 1.1) or acetate buffer (pH 4.5). The release of threonic acid over time was measured using HPLC. Figure 7 The release profiles at pH 1.1 and 4.5 are shown in

[0186] Example 2

[0187] Preparation and dissolution profiles of sustained-release tablets.

[0188] Examples of sustained-release tablets (Formulation B) are discussed. Tablets of Formulation B (i.e., sustained-release tablets) contain magnesium L-threonate as a magnesium composition, carnauba wax as a binder, magnesium stearate as a lubricant, and a coating material that contains talc as an inert powder and hydrogenated vegetable oil. The weight ratio of carnauba wax to magnesium stearate is 20. Preparations with 450 mg of magnesium L-threonate were also made with the same excipients otherwise.

[0189] Ingredient Mg / tablet %, weight / weight Magnesium threonate 500 70.42 Carnauba wax 200 28.17 Magnesium stearate, NF 10 1.41 Total amount 710 100.00

[0190] In a USP Type II (paddle) dissolution system, the release profiles of the tablets of Formulation B prepared above were examined at 75 rpm at a temperature of about 37 °C in 0.1 N HCl (pH 1.1), acetate buffer (pH 4.5), or phosphate buffer (pH 6.8). The release of threonic acid over time was measured using HPLC. Figure 1A , Figure 1B andFigure 1C Release curves at pH 1.1 (designated as 114), 4.5 (designated as 124), and 6.8 (designated as 144) are shown.

[0191] Example 3

[0192] Preparation and dissolution curves of controlled-release tablets.

[0193] Another example (Formulation C) of a sustained-release tablet formulation is discussed. The tablets of Formulation C (i.e., controlled-release tablets) contain magnesium L-threonate, povidone K-90 as a binder, microcrystalline cellulose as a glidant, colloidal silicon dioxide as a filler, carbopol and carboxymethyl cellulose as swellable materials, Starcap starch, magnesium stearate as a lubricant, and talc as an inert powder.

[0194]

[0195] In a USP Type II (paddle) dissolution system, the release curves of the tablets of Formulation C prepared above were examined at 75 rpm at a temperature of about 37 °C in 0.1 N HCl (pH 1.1) or acetate buffer (pH 4.5). The release amount of threonic acid over time was measured using HPLC. The release amount of magnesium over time was measured using ICP-MS. Figure 1A , Figure 1B and Figure 1D Release curves at pH 1.1 (designated as 116) and 4.5 (designated as 126) are shown.

[0196] Example 4

[0197] Pharmacokinetic study of magnesium threonate dosage

[0198] This example compared the fluctuation indices of three dosage forms (Formulation A, Formulation B, and Formulation C) containing magnesium threonate. Compared with an immediate-release dosage form (Formulation A), the extended-release dosage forms (Formulation B and Formulation C) were designed to promote slower release of the active agents (magnesium and / or threonic acid). The extended-release dosage forms were designed to provide sufficient exposure of the active agents for once-daily or twice-daily dosing.

[0199] Subjects and methods

[0200] The L-threonic acid concentration in the plasma of subjects administered a single dosage form (three tablets) of Formulation A, Formulation B, or Formulation C was determined by HPLC. In a randomized crossover manner, each of 12 male subjects received 1350 mg or 1500 mg of Formulation A, Formulation B, and Formulation C (washout period of 3 days). Plasma was collected from subjects who received a single dosage form in a fasting or fed state after a meal. Fourteen plasma samples were collected for each subject at the time of dosage form administration within 24 hours.

[0201] Generate PK curves using plasma concentrations and calculate the total exposure (AUC 0-24 ) of magnesium L-threonate within 24 hours, the peak plasma concentration (C max ) of L-threonic acid, the time (T max ) to reach the peak plasma concentration of L-threonic acid, and the terminal half-life (T 1 / 2 ). The values presented in Table 2 are the averages of all subjects who completed administration of all three formulations. Normalize the AUC 0-24 and C max values to an effective dose of 1500 mg. Multiply any AUC 0-24 or C max values from subjects who received the 1350 mg dosage form (three tablets each containing 450 mg of magnesium L-threonate) by 10 and divide by 9. Both C max and T max are observed values rather than calculated. In other words, among all blood sampling time points, for each subject, consider the highest analyzed concentration as C max , and consider the corresponding time point as T max . Calculate the AUC 0-24 for each subject using the rectangular method and perform left-endpoint approximation using all time points at which plasma concentrations were obtained from 0 to 24 hours. The following equation is used to calculate T 1 / 2 :

[0202]

[0203] where k e is the elimination rate constant;

[0204] C is the plasma concentration in μg / mL; and

[0205] t is the time in hours (h).

[0206] To calculate the fluctuation value and skewness of each curve, generate a theoretical steady-state plot to simulate repeated dosing every 12 hours. To calculate the fluctuation index, use the concentration data for the first 12 hours (dosing interval) after dosing. Calculate the estimated fluctuation of the plasma concentration of L-threonic acid by subtracting the steady-state minimum concentration from the steady-state maximum concentration. Steady state is theoretically reached in approximately 24 hours.

[0207] Skewness is a measure of the asymmetry of the distribution around its mean, calculated using the Excel SKEW function. Positive skewness indicates a distribution with an asymmetric tail extending towards larger positive values, while negative skewness indicates a distribution with an asymmetric tail extending towards larger negative values. To use the Excel SKEW function, the x-axis needs to be evenly distributed. Therefore, within 12 hours (from 12 to 36 hours starting from the steady-state curve), the y-value is estimated every 1 hour for the x-value.

[0208] Table 2

[0209]

[0210]

[0211] Table 3 shows the concentrations calibrated by the concentration of the treatment dose per patient. The upper table shows the data obtained from the pharmacokinetic study (24 mg / kg LBM / dose). Table 3 shows the values calibrated by 17.5 mg / kg LBM / dose.

[0212] Table 3

[0213]

[0214] Example 5

[0215] Dose estimation.

[0216] This example compares the doses of magnesium L-threonate provided in the dosage form. Based on the total body weight (TBW) of each subject and the lean body mass (LBM) of each subject, the effect of magnesium L-threonate treatment on human cognitive ability is evaluated through a threshold.

[0217] In two experiments, male and female subjects received the dosage form containing magnesium L-threonate daily for 9 - 12 weeks. In the first experiment, the dose of the dosage form was set to approximately 1.5 g of magnesium L-threonate per day (1.5 g / day) for subjects with a TBW between 50 and 70 kg, and approximately 2 g of magnesium L-threonate per day (2 g / day) for subjects with a TBW between 70 and 100 kg. Male and female subjects between 50 - 70 years old were administered magnesium L-threonate for 12 weeks. After administering magnesium L-threonate, the efficacy in improving overall cognitive ability was determined by the change in performance in the Neuropsychological Test Battery (NTB), which consists 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 combined standardized scores (z-scores) from individual cognitive tests for the clinical test group.

[0218] In a second experiment, male and female schizophrenic patients between the ages of 18 and 55 received 2 g of magnesium L-threonate (2 g / day) daily. After 9 weeks of administration of magnesium L-threonate, efficacy in improving overall cognitive ability was determined by changes in performance on the MATRICS Consensus Cognitive Battery (MCCB). The MCCB can also be expressed as a z-score.

[0219] To evaluate the overall effect of magnesium L-threonate in the two studies, data from the two studies were combined using the change in z-value relative to baseline. Subjects were divided into a high-dose group and a low-dose group, which were defined based on the median dose per day for all subjects in the two studies in terms of TBW and LBM. The median dose per day in terms of TBW was approximately 24 mg / kg TBW / day, and the median dose per day in terms of LBM was approximately 35 mg / Kg LBM / day. When classifying subject scores by high and low doses in terms of TBW, subjects receiving the high-dose drug (greater than 24 mg / kg TBW / day) did not perform better than subjects receiving the low-dose drug (less than 24 mg / kg TBW / day) ( Figure 4 , Figure 410). Alternatively, when classifying subject scores by high and low doses in terms of LBM, subjects receiving the high-dose drug (greater than 35 mg / kg LBM / day) showed significantly greater improvement in overall cognitive ability than subjects receiving the low-dose drug (less than 35 mg / kg LBM / day) ( Figure 4 , Figure 420).

[0220] A two-sample T-test was used to compare the efficacy of 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). On the other hand, as shown in Table 5, when calibrated by 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 calibrated by LBM.

[0221] Table 4

[0222]

[0223] Table 5

[0224]

[0225] Example 6

[0226] Improving Mood and Cognition

[0227] This example compares the in vivo efficacy of two dosage forms (Formulation A and Formulation B) containing magnesium threonate, which exhibit different in vivo plasma concentration curves. Formulation B exhibits a lower fluctuation index compared to Formulation A and Formulation C disclosed herein and exhibits a lower skewness. The two dosage forms were compared in terms of improving mood and cognition in human subjects.

[0228] Subjects and Methods

[0229] A single-center, double-blind, randomized, four-way crossover study was conducted in 22 healthy male and female subjects aged 35 - 72 years (inclusive). Subjects who gave informed consent completed an online questionnaire to evaluate their sleep, mood, and cognitive abilities. Subjects with subjective sleep and mood discomfort were included. Sleep discomfort needed to include problems with sleep maintenance.

[0230] The dose was based on the subject's lean body mass (LBM). For a single dose administered only at night, the dose was approximately 20 mg / kg LBM / day (half of the dose of 40 mg / kg LBM / day for the whole day). Subjects received treatment with L-magnesium threonate or placebo for 5 days in random order, with a washout period of 2 days between each. Each study cycle, including the washout period, was one week long.

[0231] Cycle A: Baseline (no administration for one week)

[0232] Cycle B: Single nocturnal dose of L-magnesium threonate Formulation A (1 - 3 tablets of 450 mg).

[0233] Cycle C: Placebo matching Formulation A

[0234] Cycle D: Single nocturnal dose of L-magnesium threonate Formulation B (1 - 3 tablets of 450 mg)

[0235] Cycle E: Placebo matching Formulation B

[0236] The study duration was 35 days (last diary entry from Day 1 to Day 35). Subjects completed daily sleep and mood diaries in the morning and evening and at the end of each dosing cycle (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 (backward), and Digit Symbol Substitution Test (DSST).

[0237] The daily sleep diary included morning questions about sleep quality and feeling refreshed, and evening questions about mood (anxiety and depression), external factors affecting mood (emotional events and workload). All diaries were completed online within one hour of going to sleep and waking up each day. Cognitive tests were completed online on Day 6 of each study cycle.

[0238] Statistical methods

[0239] 15 subjects were included in the data analysis - completed the study and the subjects whose dosages were in accordance with the protocol throughout the study. Individual cognitive test scores were converted to standardized z scores. The z scores were calculated using the baseline values ​​of the study population. In order to generate the comprehensive cognitive score of the subject, the z scores of the subjects in the three tests were averaged at each time point. The comprehensive cognitive scores of all subjects in 5 cycles (baseline period and 4 application periods) were compared by a multi-layer linear model. A general linear model (SPSS statistics subscription software) with treatment as a fixed factor and age, gender, and mood as covariates was used. Using all the values ​​of each subject, the anxiety and depression problems in the daily sleep diary were converted to the z scores of each subject. By taking the average value from the 3rd day to the 5th day, the anxiety and depression scores of each cycle were calculated. In each study cycle, the anxiety and depression z scores of each subject were averaged to generate mood z scores. The mood scores of different applications (baseline, MgT formula A, formula B, placebo A, placebo B) were compared by a multi-layer linear model, in which treatment was a fixed factor, and daily emotional load, workload, and sleep quality were covariates. p less than 0.05 was considered significant. The results of this study are shown in Figure 5A - Figure 5C .

[0240] Example 7

[0241] Tablet preparation and dissolution profile

[0242] Another example of a tablet dosage form (Formulation D) having a two-part intragranular component and having an extragranular component was prepared as shown in Table 6.

[0243] Table 6

[0244]

[0245] Tablets are prepared by pre-blending part 1 and part 2 of the intragranular ingredients. Each part is then roller compacted and the parts are combined. The extragranular part is then added and tablets are formed using a production-scale tablet press at normal compression pressure.

[0246] The release profile of the tablets of Formulation D prepared above was examined in a USPI Type II (paddle) dissolution system at 75 rpm at a temperature of about 37°C in 0.1N HCl (pH 1.1) or acetate buffer (pH 4.5). The amount of threonate released over time was measured using HPLC. The release profile is shown in Figure 6 middle.

[0247] Another example of preparing a tablet dosage form (Formulation D) having components within a single-particulate and having extra-particulate components is shown in Table 7.

[0248] Table 7

[0249]

[0250] Table 8 provides the dissolution data for the above formulations.

[0251] Table 8

[0252]

[0253] Specifically, the present invention relates to the following technical solutions:

[0254] 1. A dosage form comprising magnesium threonate, the dosage form being for treating a disease, disorder, syndrome, and / or condition in a patient in need thereof, wherein:

[0255] (a) At least a portion of the magnesium (Mg) and threonate (T) of the magnesium threonate is present in the form of the salt MgT2;

[0256] (b) The magnesium threonate is present in an amount between about 200 and 6000 mg;

[0257] (c) When administered to the patient in need thereof, the dosage form is sufficient to provide an in vivo plasma profile of threonic acid, the in vivo plasma profile including an average C between about 5 μg / mL and about 20 μg / mL avg .

[0258] 2. The dosage form according to technical solution 1, wherein the in vivo plasma profile from the dosage form exhibits a fluctuation index of less than about 170%.

[0259] 3. The dosage form according to technical solution 1 or 2, wherein the in vivo plasma profile from the dosage form exhibits an average T of at least about 4.5 hours max .

[0260] 4. A dosage form comprising magnesium threonate, wherein:

[0261] (a) At least a portion of the magnesium (Mg) and threonate (T) of the magnesium threonate is present in the form of the salt MgT2;

[0262] (b) The magnesium threonate is present in an amount between about 200 and 6000 mg; and

[0263] (c) The in vivo plasma profile from the dosage form exhibits a fluctuation index of less than about 170%.

[0264] 5. The dosage form according to any one of Technical Solutions 1 to 4, wherein the in vivo plasma profile from said dosage form exhibits a skewness of less than about 0.2.

[0265] 6. A dosage form comprising magnesium threonate, wherein:

[0266] (a) At least a portion of the magnesium (Mg) and threonate (T) of said magnesium threonate is present in the form of the salt MgT2;

[0267] (b) The magnesium threonate is present in an amount between about 200 and 6000 mg; and

[0268] (c) The in vivo plasma profile from said dosage form exhibits a skewness of less than about 0.2.

[0269] 7. A dosage form comprising magnesium threonate, wherein:

[0270] (a) At least a portion of the magnesium (Mg) and threonate (T) of said magnesium threonate is present in the form of the salt MgT2;

[0271] (b) The magnesium threonate is present in an amount between about 200 and 6000 mg; and

[0272] (c) The release of said magnesium threonate from said dosage form exhibits a first-order release constant between about 0.2 h -1 and 0.6 h -1 which is calculated from the measured values obtained using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of about 37 °C.

[0273] 8. The dosage form according to Technical Solution 7, wherein the first-order release constant is between 0.25 h -1 and 0.45 h -1 between.

[0274] 9. The dosage form according to Technical Solution 7, wherein the first-order release constant is between 0.3 h -1 and 0.4 h -1 between.

[0275] 10. The dosage form according to any one of the foregoing technical solutions, wherein the dosage form is orally administered to the patient.

[0276] 11. The dosage form according to any one of the foregoing technical solutions, wherein the dosage form is administered to a patient in a fed state.

[0277] 12. The dosage form according to any one of the foregoing technical solutions, wherein it is administered once every 12 hours to a patient in need of treating a disease, disorder, syndrome, and / or condition, and the dosage form is sufficient to provide at least about 15 mg / kg of lean body mass / dose of magnesium threonate.

[0278] 13. The dosage form according to any one of the foregoing technical solutions, wherein it is administered once every 12 hours to a patient in need of treating a disease, disorder, syndrome, and / or condition, and the dosage form is sufficient to provide about 10 to 30 mg / kg of lean body mass / dose of magnesium threonate.

[0279] 14. The dosage form according to any one of technical solutions 1 to 12, wherein in a patient in need of treating a disease, disorder, syndrome, and / or condition, the dosage form is sufficient to provide at least about 15 mg / kg of lean body mass / dose / day of magnesium threonate.

[0280] 15. The dosage form according to any one of technical solutions 1 to 12, wherein the dosage form is sufficient to provide about 20 to 60 mg / kg of lean body mass / day of magnesium threonate.

[0281] 16. The dosage form according to any one of technical solutions 1 to 12, wherein the dosage form is sufficient to provide at least about 30 mg / kg of lean body mass / day of magnesium threonate.

[0282] 17. The dosage form according to any one of the foregoing technical solutions, wherein the magnesium threonate is present in an amount between about 40% and about 77% weight / weight.

[0283] 18. The dosage form according to any one of the foregoing technical solutions, wherein the magnesium threonate is present in an amount between about 45% and about 70% weight / weight.

[0284] 19. The dosage form according to technical solution 18, wherein the magnesium threonate is present in an amount of about 70%.

[0285] 20. The dosage form according to technical solution 18, wherein the magnesium threonate is present in an amount of about 53%.

[0286] 21. The dosage form according to any one of the foregoing technical solutions, further comprising carnauba wax.

[0287] 22. The dosage form according to technical solution 21, wherein the carnauba wax is present in an amount between about 10% and about 30% weight / weight.

[0288] 23. The dosage form according to technical solution 22, wherein the carnauba wax is present in an amount of about 10% weight / weight.

[0289] 24. The dosage form according to technical solution 22, wherein the carnauba wax is present in an amount of about 28% weight / weight.

[0290] 25. The dosage form according to any one of the foregoing technical solutions further comprises magnesium stearate.

[0291] 26. The dosage form according to technical solution 25, wherein the magnesium stearate is present in an amount between about 1% and about 3% weight / weight.

[0292] 27. The dosage form according to technical solution 25, wherein the magnesium stearate is present in an amount between about 1% and about 2% weight / weight.

[0293] 28. The dosage form according to technical solution 25, wherein the magnesium stearate is present in an amount of about 1.4% weight / weight.

[0294] 29. The dosage form according to technical solution 25, wherein the magnesium stearate is present in an amount of about 2% weight / weight.

[0295] 30. The dosage form according to technical solution 25, wherein the weight ratio of carnauba wax to magnesium stearate is greater than about 12.

[0296] 31. The dosage form according to technical solution 25, wherein the weight ratio of carnauba wax to magnesium stearate is about 20.

[0297] 32. The dosage form according to any one of the above technical solutions, wherein the dosage form comprises an inner part of the granule and an outer part of the granule.

[0298] 33. The dosage form according to technical solution 25, wherein the weight ratio of carnauba wax to magnesium stearate in the inner part of the granule is between about 5 and about 12.

[0299] 34. The dosage form according to technical solution 33, wherein the weight ratio of carnauba wax to magnesium stearate in the inner part of the granule is about 8.

[0300] 35. The dosage form according to technical solution 33, wherein the weight ratio of carnauba wax to magnesium stearate in the inner part of the granule is about 10.

[0301] 36. The dosage form according to any one of the foregoing technical solutions, wherein the dosage form is liquid, semi-liquid, semi-solid or solid.

[0302] 37. The dosage form according to any one of technical solutions 1 to 35, wherein the dosage form is a gel, pill, tablet, capsule, bead, emulsion, granule, paste, pellet, powder, syrup, suspension, slurry or aerosol.

[0303] 38. The dosage form according to any one of the foregoing technical solutions further comprises an additional reagent.

[0304] 39. The dosage form according to embodiment 38, wherein the additional reagent is a pharmaceutically acceptable excipient.

[0305] 40. The dosage form according to embodiment 39, wherein the pharmaceutically acceptable excipient is selected from the group consisting of binders, fillers, lubricants, dissolution aids, and any combination thereof.

[0306] 41. The dosage form according to embodiment 39, wherein the pharmaceutically acceptable excipient is selected from the group consisting of lactose, microcrystalline cellulose, silica, titanium dioxide, stearic acid, starch, sodium starch glycolate, polyvinylpyrrolidone, pregelatinized starch, crosslinked carboxymethylcellulose, ethylcellulose, dicalcium phosphate, talc, sucrose, calcium stearate, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, hydrogenated vegetable oil, beeswax, and any combination thereof.

[0307] 42. A method of treating a disease, disorder, syndrome, and / or condition in a patient in need thereof, the method comprising orally administering the dosage form according to any one of embodiments 1 to 38.

[0308] 43. The method according to embodiment 42, wherein the dosage form is sufficient to provide at least about 15 mg / kg lean body mass / dose of MgT2 to a patient suffering from a disease, disorder, syndrome, and / or condition.

[0309] 44. The method according to embodiment 42 or 43, further comprising:

[0310] (a) determining the physiological concentration of threonic acid in the patient before administering the dosage form; and

[0311] (b) determining at least one other physiological concentration of threonic acid in the patient after orally administering the dosage form.

[0312] 45. The method according to embodiment 44, wherein the physiological concentration is serum concentration, plasma concentration, urine concentration, or cerebrospinal fluid concentration.

[0313] 46. The method according to any one of embodiments 42 to 45, wherein the dosage form is administered twice daily with food.

[0314] 47. The method according to any one of embodiments 42 to 45, wherein the patient is suffering from a disease, disorder, syndrome, and / or condition selected from the group consisting of cardiovascular diseases, neurodegenerative disorders, sleep disorders, neurological disorders, nerve injuries, developmental disorders / autism spectrum disorders, autoimmune diseases, genetic diseases, rheumatic diseases, inflammatory diseases, neuropsychiatric disorders, cancer, addictions, and physical traumas.

[0315] 48. The method according to any one of technical solutions 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 disorder, stress, anxiety disorder, depression, sleep disorder, psychosis, metabolic disorder, fatigue, cancer, HIV, hepatitis, spinal cord injury, postoperative recovery, post-traumatic stress disorder, arthritis, neuropathic pain, inflammation, tremor, and fibromyalgia.

[0316] 49. A method for preparing a dosage form according to any one of technical solutions 1 - 41, the method comprising:

[0317] (a) forming a mixture comprising the magnesium threonate and additional reagents, wherein at least a portion of the magnesium (Mg) and threonate (T) of the magnesium threonate is present in the form of the salt MgT2; and

[0318] (b) formulating the mixture to form the dosage form.

[0319] Although the preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. It is not intended to limit the present invention by the specific examples provided in the specification. Although the present invention has been described with reference to the foregoing specification, the description and illustration of the embodiments herein are not intended to be construed in a limiting sense. Many changes, variations, and substitutions will now occur to those skilled in the art without departing from the present invention. In addition, it should be understood that all aspects of the present invention are not limited to the specific descriptions, configurations, or relative proportions set forth herein, which depend on various conditions and variables. It should be understood that various alternatives to the embodiments of the present invention described herein may be used to practice the present invention. Therefore, it is contemplated that the present invention should also cover any such alternatives, modifications, variations, or equivalent forms. It is intended that the following claims define the scope of the present invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. A dosage form comprising magnesium threonate, which is used for treating diseases, disorders, syndromes, and / or conditions in patients in need thereof, wherein: (a) At least a portion of the magnesium (Mg) and threonate (T) of the magnesium threonate exists in the form of the salt MgT2; (b) The magnesium threonate is present in an amount between about 200 and 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, the in vivo plasma profile comprising an average C between about 5 µg / mL and about 20 µg / mL avg .

2. The dosage form according to claim 1, wherein the in vivo plasma profile from the dosage form exhibits a fluctuation index of less than about 170%.

3. The dosage form according to claim 1 or 2, wherein the in vivo plasma profile from the dosage form exhibits an average T of at least about 4.5 hours max .

4. A dosage form comprising magnesium threonate, wherein: (a) At least a portion of the magnesium (Mg) and threonate (T) of the magnesium threonate exists in the form of the salt MgT2; (b) The magnesium threonate is present in an amount between about 200 and 6000 mg; and (c) The in vivo plasma profile from the dosage form exhibits a fluctuation index of less than about 170%.

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

2.

6. A dosage form comprising magnesium threonate, wherein: (a) At least a portion of the magnesium (Mg) and threonate (T) of the magnesium threonate exists in the form of the salt MgT2; (b) The magnesium threonate is present in an amount between about 200 and 6000 mg; and (c) The in vivo plasma profile from the dosage form exhibits a skewness of less than about 0.

2.

7. A dosage form comprising magnesium threonate, wherein: (a) At least a portion of the magnesium (Mg) and threonate (T) of the magnesium threonate exists in the form of the salt MgT2; (b) The magnesium threonate is present in an amount between about 200 and 6000 mg; and (c) The release of the magnesium threonate from the dosage form exhibits a first-order release constant between about 0.2 h -1 and 0.6 h -1 which is calculated from measurements obtained using a USP Type II (paddle) dissolution system at 75 rpm at a temperature of about 37 °C.

8. The dosage form according to claim 7, wherein the first-order release constant is between 0.25 h -1 and 0.45 h -1 .

9. The dosage form according to claim 7, wherein the first-order release constant is between 0.3 h -1 and 0.4 h -1 .

10. The dosage form according to any one of the preceding claims, wherein the dosage form is orally administered to the patient.

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