Sustained Release Composition of α-Ketoglutaric Acid Compounds

Abstract

In certain embodiments, sustained release compositions of α-ketoglutaric acid compounds are described herein.

Description

BACKGROUND OF THE INVENTION

[0001] α-Ketoglutaric acid is an important biomolecule, a key intermediate of the Krebs cycle, a nitrogen transporter, and a cosubstrate of molecular oxidation. The α-ketoglutarate anion plays a key role in metabolism, mainly in aerobic organisms. Calcium α-ketoglutarate (Ca-AKG) is an important source of the α-ketoglutarate anion. Currently available Ca-AKG is formulated for immediate release. This known delivery method releases Ca-AKG in a very short time, which results in peak blood concentrations, faster excretion, and an increased frequency of CaAKG administration. Therefore, there is a need to discover alternative methods for delivering Ca-AKG. SUMMARY OF THE INVENTION

[0002] Unexpectedly, it has been found that when α-ketoglutaric acid compounds are released early in the stomach or in the upper gastrointestinal (GI) tract, the overall bioavailability of the α-ketoglutaric acid compounds is variable and / or low, resulting in less predictable dose guidance and less predictable clinical outcomes. Controlled release, sustained release, and / or delayed release formulations of Ca-AKG have been discovered. Formulations of α-ketoglutaric acid compounds with modified release characteristics including controlled release, sustained release, and / or delayed release properties are described herein. In an illustrative embodiment of the present invention, compositions are described herein that comprise

[0003] (a) a therapeutically effective amount of calcium α-ketoglutarate, and

[0004] (b) a controlled release matrix.

[0005] Illustratively, the composition is characterized by being capable or configured to provide a calcium α-ketoglutarate release rate over a predetermined period of time or during a predetermined period that does not exceed 90% of the calcium α-ketoglutarate release rate of one or more calcium α-ketoglutarate compositions formulated in the absence of any controlled release matrix or formulated such that the active ingredient is otherwise released in an uncontrolled manner. Illustrative examples of calcium α-ketoglutarate compositions formulated in the absence of any controlled release matrix for comparison include, but are not limited to, Simplesa TM and Klaire Labs TM .

[0006] In another embodiment, compositions are also disclosed herein that comprise calcium α-ketoglutarate and one or more agents selected from the group consisting of: surfactants, preservatives, flavoring agents, vitamins, antioxidants, sweetening agents, and combinations thereof.

[0007] In another embodiment, compositions are also disclosed herein that comprise:

[0008] 525 mg of calcium α-ketoglutarate monohydrate;

[0009] one or more release-modifying agents;

[0010] and optionally further comprises one or more of isomaltulose, vegetable wax (carnauba wax and / or rice bran), stearic acid, magnesium stearate, and silica.

[0011] In another embodiment, a composition is also disclosed herein, comprising:

[0012] 500 - 550 mg of calcium α-ketoglutarate monohydrate;

[0013] 450 mcg of retinyl palmitate;

[0014] one or more release-modifying agents;

[0015] and optionally further comprises one or more of isomaltulose, vegetable wax (carnauba wax and / or rice bran), stearic acid, magnesium stearate, and silica.

[0016] In another embodiment, a composition is also disclosed herein, comprising:

[0017] 500 - 550 mg of calcium α-ketoglutarate monohydrate;

[0018] 12.5 mcg (500 IU) of cholecalciferol;

[0019] one or more release-modifying agents;

[0020] and optionally further comprises one or more of isomaltulose, vegetable wax (carnauba wax and / or rice bran), stearic acid, magnesium stearate, and silica.

[0021] It should be understood that in the formulations described herein, such release-modifying agents can be used to control, delay, or sustain the release of Ca-AKG, or to control, delay, or sustain the release of a combination of Ca-AKG with one or more additional components in the composition (such as a combination of Ca-AKG and one or more vitamins).

[0022] Surprisingly, it has been found that compared to formulations prepared in the absence of any controlled-release matrix or alternative formulations formulated such that the active ingredient is otherwise released in an uncontrolled manner, the formulations described herein can comprise lower doses of the active ingredient, including lower doses of AKG and / or its salts. Without being bound by theory, it is believed herein that the formulations described herein provide a higher overall bioavailability, and thus, lower doses can be administered to achieve similar results. Detailed Description

[0023] Exemplary embodiments of the present invention are described in the following clauses:

[0024] A composition comprising a unit dose or dosage form, the composition comprising (a) a therapeutically effective amount of calcium α-ketoglutarate, and (b) a controlled-release matrix.

[0025] A composition comprising a unit dose or dosage form as described in the preceding clause, wherein the controlled-release matrix comprises hydroxypropyl methylcellulose (HPMC).

[0026] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, wherein the hydroxypropyl methylcellulose (HPMC) is selected from the group consisting of HPMC having a number average molecular weight of about 22,000 - 30,000, about 68,000 - 95,000, about 115,000 - 150,000, and about 220,000 - 300,000 and combinations thereof.

[0027] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, wherein the controlled-release matrix comprises HPMC having a number average molecular weight of about 68,000 - 95,000.

[0028] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, wherein the controlled-release matrix comprises HPMC having a number average molecular weight of about 115,000 - 150,000.

[0029] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, wherein the controlled-release matrix comprises HPMC having a number average molecular weight between about 68,000 - 95,000 and about 115,000 - 150,000.

[0030] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, wherein the amount of calcium α-ketoglutarate is about 30% to about 65% by total weight of the composition; about 40% to about 65% by total weight of the composition; about 40% to about 60% by total weight of the composition; or about 45% to about 55% by total weight of the composition.

[0031] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, wherein the amount of calcium α-ketoglutarate is about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, or about 65% by total weight of the composition.

[0032] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, which comprises from about 250 to about 1000 mg of calcium α-ketoglutarate; from about 350 to about 1000 mg of calcium α-ketoglutarate; from about 400 to about 1000 mg of calcium α-ketoglutarate; from about 400 to about 900 mg of calcium α-ketoglutarate; from about 400 to about 800 mg of calcium α-ketoglutarate; from about 400 to about 700 mg of calcium α-ketoglutarate; or from about 400 to about 600 mg of calcium α-ketoglutarate.

[0033] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, which comprises about 400 mg of calcium α-ketoglutarate; about 425 mg of calcium α-ketoglutarate; about 450 mg of calcium α-ketoglutarate; about 500 mg of calcium α-ketoglutarate; about 525 mg of calcium α-ketoglutarate; about 550 mg of calcium α-ketoglutarate; about 575 mg of calcium α-ketoglutarate; or about 600 mg of calcium α-ketoglutarate.

[0034] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, which comprises about 5% dietary value of calcium; about 6% dietary value of calcium; about 7% dietary value of calcium; about 8% dietary value of calcium; about 9% dietary value of calcium; about 10% dietary value of calcium; about 11% dietary value of calcium; about 12% dietary value of calcium; about 13% dietary value of calcium; about 14% dietary value of calcium; about 15% dietary value of calcium; about 16% dietary value of calcium; about 17% dietary value of calcium; about 18% dietary value of calcium; about 19% dietary value of calcium; about 20% dietary value of calcium.

[0035] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, which further comprises one or more excipients selected from the group consisting of: one or more diluents, fillers, disintegrants, lubricants, binders, and suspending agents and combinations thereof.

[0036] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, which further comprises microcrystalline cellulose; wherein the amount of microcrystalline cellulose is from about 14% to about 27% by total weight of the composition; from about 17% to about 23% by total weight of the composition; from about 17% to about 22% by total weight of the composition; from about 17% to about 20% by total weight of the composition.

[0037] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, which further comprises lactose monohydrate; wherein the amount of lactose monohydrate is from about 6% to about 19% by total weight of the composition; from about 8% to about 17% by total weight of the composition; from about 10% to about 15% by total weight of the composition; from about 11% to about 14% by total weight of the composition.

[0038] A composition comprising a unit dose or dosage form as described in any of the foregoing clauses, further comprising one or more lubricants; wherein the lubricant is magnesium stearate; wherein the amount of magnesium stearate is about 1% to about 5% by total weight of the composition; about 1% to about 3% by total weight of the composition; about 2% to about 4% by total weight of the composition.

[0039] A composition comprising a unit dose or dosage form as described in any of the foregoing clauses, further comprising one or more disintegrants; wherein the disintegrant is silicon dioxide; wherein the amount of silicon dioxide is about 1% to about 5% by total weight of the composition; about 1% to about 3% by total weight of the composition; about 2% to about 4% by total weight of the composition.

[0040] A composition comprising a unit dose or dosage form as described in any of the foregoing clauses, further comprising a sweetening agent; wherein the sweetening agent is isomaltulose.

[0041] A composition comprising a unit dose or dosage form as described in any of the foregoing clauses, further comprising a wax; wherein the wax is carnauba wax and / or rice bran wax.

[0042] A composition comprising a unit dose or dosage form as described in any of the foregoing clauses, further comprising one or more agents selected from the group consisting of: surfactants, preservatives, flavoring agents, vitamins, antioxidants, and sweetening agents.

[0043] A composition comprising a unit dose or dosage form as described in any of the foregoing clauses, further comprising one or more vitamins or analogs or derivatives thereof; wherein the vitamin is nicotinamide riboside (NR); wherein the vitamin is nicotinamide mononucleotide (NMN).

[0044] A composition comprising a unit dose or dosage form as described in any of the foregoing clauses, further comprising an antioxidant; wherein the antioxidant is fisetin.

[0045] A composition comprising a unit dose or dosage form as described in any of the foregoing clauses, wherein the composition is characterized in that the release rate of calcium α-ketoglutarate is uncontrolled or about 90% or less of the calcium α-ketoglutarate release rate of a calcium α-ketoglutarate composition formulated in the absence of a controlled release matrix; about 70% or less of the calcium α-ketoglutarate release rate of a calcium α-ketoglutarate composition formulated in the absence of a controlled release matrix; about 60% or less of the calcium α-ketoglutarate release rate of a calcium α-ketoglutarate composition formulated in the absence of a controlled release matrix; about 50% or less of the calcium α-ketoglutarate release rate of a calcium α-ketoglutarate composition formulated in the absence of a controlled release matrix; about 40% or less of the calcium α-ketoglutarate release rate of a calcium α-ketoglutarate composition formulated in the absence of a controlled release matrix; 45% or less of the calcium α-ketoglutarate release rate of a calcium α-ketoglutarate composition formulated in the absence of a controlled release matrix; about 30% or less of the calcium α-ketoglutarate release rate of a calcium α-ketoglutarate composition formulated in the absence of a controlled release matrix.

[0046] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, wherein the composition is characterized in that the release rate of calcium α-ketoglutarate is about 30% or less after a time between about 0.5 and about 2 hours in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; the release rate of calcium α-ketoglutarate is about 25% or less after a time between about 0.5 and about 1.5 hours in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; the release rate of calcium α-ketoglutarate is about 25% or less about 1 hour after in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; the release rate of calcium α-ketoglutarate is about 20% or less about 1 hour after in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; the release rate of calcium α-ketoglutarate is about 60% or less after a time between about 4 and about 8 hours in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; the release rate of calcium α-ketoglutarate is about 60% or less about 8 hours after in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; the release rate of calcium α-ketoglutarate is about 60% or less after a time between about 4 and about 6 hours in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; or the release rate of calcium α-ketoglutarate is about 60% or less about 6 hours after in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C.

[0047] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, wherein the composition is characterized in that the release rate of calcium α-ketoglutarate is about 75% or higher after a time between about 10 and about 11 hours in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37 °C; the release rate of calcium α-ketoglutarate is about 75% or higher after about 10 hours in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37 °C; the release rate of calcium α-ketoglutarate is about 75% or higher after a time between about 9 and about 11 hours in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37 °C; the release rate of calcium α-ketoglutarate is about 75% or higher after about 9 hours in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37 °C; the release rate of calcium α-ketoglutarate is about 90% or higher after a time between about 12 and about 15 hours in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37 °C; the release rate of calcium α-ketoglutarate is about 90% or higher after a time between about 12 and about 14 hours in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37 °C; the release rate of calcium α-ketoglutarate is about 90% or higher after about 13 hours in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37 °C; or the release rate of calcium α-ketoglutarate is about 90% or higher after about 12 hours in a dissolution medium, as measured by a paddle apparatus having a basket rotating at 75 rpm, wherein the dissolution medium is about 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37 °C.

[0048] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, wherein the calcium α-ketoglutarate is calcium α-ketoglutarate monohydrate.

[0049] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, which comprises 525 mg of calcium α-ketoglutarate monohydrate.

[0050] A composition comprising a unit dose or dosage form as described in any of the preceding clauses, wherein the dose unit is configured for oral administration; the dose unit is a tablet; the dose unit is a capsule.

[0051] A unit dose comprising 525 mg of Ca-AKG monohydrate and a controlled release matrix, isomaltulose, one or more vegetable waxes, stearic acid, magnesium stearate, silica, wherein the controlled release matrix comprises HPMC.

[0052] A unit dose as described in any of the preceding clauses, which further comprises a coating as described herein.

[0053] The natural decline with age and the pharmacological treatment and prevention of diseases associated with aging (aging) have posed challenges to the medical community, in part because the agents used for this purpose require strict characteristics. The aging patient population places an unusually high burden on drug therapies that are bioavailable, non-toxic, and have no long-term side effects. Prevention requires treating patients who may be at risk of developing age-related conditions but are asymptomatic or have mild symptoms, and requires agents that do not compromise existing health. The treatment of patients with existing age-related diseases has high requirements for non-toxicity so as not to worsen the existing health condition. In addition, the treatment or prevention of age-related conditions generally may require treatment with agents for many years, and thus requires that such agents have no cumulative toxicity or long-term harmful effects on organ systems.

[0054] Recent findings suggest that aging is driven by molecular programs operating in animals, rather than just by the accumulation of molecular damage. Human and model organism studies aimed at elucidating the molecular mechanisms of aging have demonstrated the existence of widely conserved longevity pathways. Various studies have shown that dietary restriction, fasting, or caloric restriction can increase the lifespan of a variety of organisms, including all major model systems described herein, and delay the appearance of multiple age-related phenotypes in that organism.

[0055] In particular, the mTOR signaling pathway has emerged as a central pro-aging pathway that is inhibited due to the life-prolonging effects of dietary restriction in yeast, nematodes, and fruit flies. In response to nutrient depletion, mTOR activity decreases and this leads to downstream events that have been shown to promote longevity and enhance resistance to environmental stressors by activating changes in gene transcription and protein translation and by altering the regulation of mTOR substrates through phosphorylation. Further, dietary restriction is known to affect not only mTOR, but also the aging process (such as the AMPK pathway (activation), the sirtuin pathway (high protein levels), mitochondrial bioenergetics (activation), and the IGF-1 pathway (inhibition)).

[0056] In some embodiments, Ca-AKG regulates the mTOR pathway. In some embodiments, Ca-AKG regulates the AMPK pathway. In some embodiments, Ca-AKG regulates both the mTOR pathway and the AMPK pathway.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0058] As used herein, unless otherwise expressly stated, the singular includes the plural. It must be noted that, unless the context clearly dictates otherwise, as used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents. In this application, unless otherwise stated, the use of "or" means "and / or". Further, the use of the term "including" and other forms such as "include", "includes", and "included" is not limiting.

[0059] "Alpha-ketoglutarate", "α-ketoglutarate", or "AKG" includes derivatives of alpha-ketoglutarate (such as those described in MacKenzie et al. (2007) Mol Cell Biol 27(9):3282-3289), analogs of alpha-ketoglutarate (such as those cited in Bunik et al. (2005) Biochemistry 44(31):10552-61), esters of alpha-ketoglutaric acid (such as dimethyl alpha-ketoglutarate and octyl alpha-ketoglutarate), and various species-specific analogs, such as human alpha-ketoglutarate, porcine alpha-ketoglutarate, murine alpha-ketoglutarate, bovine alpha-ketoglutarate, etc.

[0060] As used herein, the terms "individual", "subject", and "patient" mean any mammal. In some embodiments, the mammal is human. In some embodiments, the mammal is non-human. None of these terms require or are limited to circumstances characterized by the supervision (such as continuous or intermittent supervision) of a health care worker (such as a doctor, registered nurse, licensed practical nurse, physician assistant, paramedic, or hospice worker).

[0061] As used herein, ranges and amounts may be expressed as "about" a particular value or range. "About" also includes the exact amount. Thus, "about 5 μL" means "about 5 μL" and also means "5 μL". Generally, the term "about" includes amounts expected to be within experimental error.

[0062] The terms "controlled release dosage form" and "controlled release layer" are used interchangeably and are defined as such controlled release dosage forms and controlled release layers in which the time course and / or location characteristics of drug release are selected to achieve a therapeutic or convenience purpose not provided by conventional immediate release dosage forms. The rate of release of the active drug from the controlled release layer or dosage form is controlled by dosage form characteristics and / or characteristics in combination with physiological or environmental conditions, rather than by physiological or environmental conditions alone. Controlled release dosage forms are used to maintain drug plasma levels within a therapeutic window. Controlled release dosage forms of some embodiments attempt to deliver a therapeutically effective amount of the active drug in a once-daily dose such that the Cmax / Cmin ratio in plasma is less than the therapeutic index at steady state and attempt to maintain the drug level at a constant effective level to provide a therapeutic benefit over a period of time (e.g., a 24-hour period). In some embodiments, the controlled release dosage form provides a substantially constant or gradually decreasing rate of drug release to provide a plasma level that remains substantially constant over time. In some embodiments, the controlled release dosage form is designed to provide a rapid increase in the drug plasma concentration that remains substantially constant within the therapeutic range of the drug over a period of time (e.g., a 24-hour period). Alternatively, in some other embodiments, the controlled release dosage form is designed to provide a rapid increase in the drug plasma concentration that, although it may not remain constant, decreases at a rate such that the plasma concentration remains within the therapeutic range over a period of time (e.g., 24 hours).

[0063] The term "controlled release matrix" refers to a matrix, such as a polymeric matrix, that is capable of delivering a bioactive agent at a controlled rate over a period of time. Although there may be an initial burst phase, the overall release kinetics of the bioactive agent from the matrix are generally linear such that a relatively constant supply of the bioactive agent is released over the desired period of time. This period of time may vary from a few hours to several days, depending on the bioactive agent and its intended use. Generally, it is preferred that a relatively high percentage (e.g., at least about 50%, at least about 75%, at least about 90%, or at least about 95%) of the bioactive agent is released from the controlled matrix during the treatment period to avoid waste of the un-released bioactive agent. As used herein, the term "release modifier" generally refers to a component that forms at least a part of the controlled release matrix, either alone or in combination.

[0064] The term "immediate release" layer or dosage form refers to the substantially immediate release of the active agent upon administration. For example, immediate release includes, but is not limited to, contact with gastric fluid and resulting in substantially complete dissolution within about 1 hour. An immediate release component may also be referred to as an immediate release. When used in conjunction with the dissolution profiles discussed herein, the term "immediate release" refers to that portion of the dosage forms disclosed herein that delivers the active agent within a period of less than 1 hour.

[0065] As used herein, the terms "coating composition", "coat composition", "coating solution", "coat solution", "coating suspension", and "coat suspension" are used interchangeably and are defined to mean a mixture of excipients for producing a controlled-release coating. The coating composition is applied to the calcium α-ketoglutarate core to form an intermediate coating, and the intermediate coating is cured to form a controlled-release coating.

[0066] The term "effective amount", "pharmaceutically effective amount", or "therapeutically effective amount" means an amount of an agent that is non-toxic but sufficient to provide the desired biological, therapeutic, and / or prophylactic result. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of calcium α-ketoglutarate as disclosed herein or a composition comprising calcium α-ketoglutarate as disclosed herein that is required to effect a clinically significant reduction of a disease or disorder. One of ordinary skill in the art can use routine experimentation to determine the appropriate effective amount in any individual case.

[0067] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not abrogate the biological activity or properties of a compound and is relatively non-toxic, i.e., the substance does not cause undesirable biological effects when administered to an individual or does not interact with any component of a composition containing it in a harmful manner.

[0068] The term "pharmaceutically acceptable salt" refers to a form of a therapeutic agent that consists of the cationic form of the therapeutic agent combined with a suitable anion, or, in an alternative embodiment, a form of the therapeutic agent that consists of the anionic form of the therapeutic agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. Edited by P.H. Stahl and C.G. Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley VCH / VHCA, 2002. Compared with nonionic substances, pharmaceutical salts generally have higher solubility and dissolution rates in gastric and intestinal fluids and can thus be used in solid dosage forms. In addition, since their solubility tends to vary with pH, selective dissolution in one part or another of the digestive tract is possible, and this ability can be exploited as an aspect of delayed-release and sustained-release behavior. In addition, since the salt-forming molecules can be balanced in their neutral form, passage through biological membranes can be modulated.

[0069] As used herein, "treatment" or "treating" refers to a course of action used to obtain a beneficial or desired result (including, but not limited to, a therapeutic benefit and / or a prophylactic benefit) with respect to a disease, disorder, or medical condition. A therapeutic benefit means the eradication or amelioration of a potential condition being treated. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the potential condition, such that an improvement is observed in the subject, even though the subject may still be afflicted with the underlying condition. In certain embodiments, for a prophylactic benefit, the composition is administered to a subject at risk of developing a particular disease or to a subject reporting one or more physiological symptoms of a disease, even though the disease may not yet have been diagnosed.

[0070] "Therapeutic effect", as the term is used herein, encompasses the therapeutic benefit and / or prophylactic benefit as described above. Prophylactic effects include delaying or eliminating the onset of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, halting, or reversing the progression of a disease or disorder, or any combination of these.

[0071] "Pharmaceutically acceptable carriers, diluents or excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that has been approved by the United States Food and Drug Administration for use in humans or livestock.

[0072] α-ketoglutaric acid compounds (AKG)

[0073] This document describes sustained release compositions of α-ketoglutaric acid compounds.

[0074] In certain aspects, the present disclosure provides compositions comprising compounds (such as α-ketoglutarates) that are edible by humans without FDA approval or are generally recognized as safe (GRAS). Such compounds are so classified because they: a) are present in the FDA SCOGS database and are generally recognized as safe by the United States Food and Drug Administration; or b) are derived from plants (such as fruits, vegetables, herbs) present in traditional diets and are thus considered safe for human consumption by the scientific community. In some embodiments, GRAS compounds are those that are edible by humans without FDA approval.

[0075] In some embodiments, the compositions disclosed herein comprise AKG. Alpha-ketoglutaric acid compounds or α-ketoglutaric acid compounds (Formula 1) are also known as 2-oxoglutaric acid, 2-ketoglutaric acid, 2-oxopentanedioic acid, and oxoglutaric acid. At physiological pH, α-ketoglutaric acid compounds exist in one or more deprotonated forms, such as those depicted as Formula 2. α-Ketoglutaric acid compounds are intermediates in the Krebs cycle of eukaryotes and are biosynthesized in such organisms from isocitric acid compounds (during the Krebs cycle) or L-glutamic acid compounds (by alanine transaminase). Both α-ketoglutaric acid compounds and their corresponding salts are commercially available by preparation from fermentation cultures (see, for example, US 2,776,926) or chemical synthesis from closely related compounds.

[0076]

[0077] Consistent with its role in energy production via the Krebs cycle, α-ketoglutaric acid compounds are important regulators of bioenergetics in cells and are considered inhibitors of ATP synthase subunit β and indirect inhibitors of the kinase mTOR, which is a result of partial inhibition of the mitochondrial electron transport chain.

[0078] In some embodiments, the α-ketoglutaric acid compounds are provided in the form of the free acid (α-ketoglutaric acid). In some embodiments, the α-ketoglutaric acid compounds are provided in the form of a mono-salt or a di-salt. In other embodiments, the α-ketoglutaric acid compounds are provided in the form of a monosodium salt, a disodium salt, a monopotassium salt or a dipotassium salt. In further embodiments, the α-ketoglutaric acid compounds are provided in the form of a mono-valent or divalent salt with other cations described in the US FDA Orange Book. Such cations include calcium, diolamine, lithium, lysine, magnesium, meglumine, ethanolamine, tromethamine and zinc. In further embodiments, the salts of α-ketoglutaric acid are provided in the form of an anhydrous salt, a hemihydrate, a monohydrate or a dihydrate.

[0079] In certain aspects, the present disclosure further provides compositions comprising α-ketoglutarate salts. In some embodiments, the α-ketoglutaric acid compounds are provided in the form of a calcium salt (Ca-AKG). In some embodiments, calcium α-ketoglutarate may be calcium α-ketoglutarate hydrate. In some embodiments, calcium α-ketoglutarate may be calcium α-ketoglutarate monohydrate. In some embodiments, calcium α-ketoglutarate may be calcium α-ketoglutarate hemihydrate. In some embodiments, calcium α-ketoglutarate may be anhydrous calcium α-ketoglutarate.

[0080] In some embodiments, the compositions disclosed herein comprise esters of α-ketoglutaric acid. In some embodiments, the ester of α-ketoglutaric acid is the methyl ester of α-ketoglutaric acid. In some embodiments, the ester of α-ketoglutaric acid is the dimethyl ester of α-ketoglutaric acid. In some embodiments, the ester of α-ketoglutaric acid is the ethyl ester of α-ketoglutaric acid. In some embodiments, the ester of α-ketoglutaric acid is the diethyl ester of α-ketoglutaric acid.

[0081] In some embodiments, the α-ketoglutaric acid compounds are provided in the form of a monolithium salt, a dilithium salt, a monosodium salt, a disodium salt, a monopotassium salt, a dipotassium salt, a calcium salt or a zinc salt. In some embodiments, the α-ketoglutaric acid compounds are provided in the form of a calcium salt. In further embodiments, the calcium salt of α-ketoglutaric acid is provided in the form of an anhydrous salt, a monohydrate or a dihydrate. In further embodiments, the α-ketoglutaric acid compounds are provided in the form of a mono-valent or divalent salt with other cations described in the US FDA Orange Book. Such cations include calcium, diolamine, lithium, lysine, magnesium, meglumine, ethanolamine, tromethamine and zinc.

[0082] Sustained release compositions of α-ketoglutaric acid compounds

[0083] In one aspect, the present disclosure describes a composition comprising a therapeutically effective amount of calcium α-ketoglutarate and a controlled-release matrix, wherein the composition is characterized by being capable of or configured to provide a rate of calcium α-ketoglutarate release over a predetermined period of time or during a predetermined period that does not exceed 90% of the rate of calcium α-ketoglutarate release of one or more calcium α-ketoglutarate compositions formulated in the absence of any controlled-release matrix.

[0084] In some embodiments, the rate of calcium α-ketoglutarate release provided by the composition does not exceed 80% of the rate of calcium α-ketoglutarate release of a calcium α-ketoglutarate composition formulated in the absence of any controlled-release matrix. In some embodiments, the rate of calcium α-ketoglutarate release provided by the composition does not exceed 70% of the rate of calcium α-ketoglutarate release of a calcium α-ketoglutarate composition formulated in the absence of any controlled-release matrix. In some embodiments, the rate of calcium α-ketoglutarate release provided by the composition does not exceed 60% of the rate of calcium α-ketoglutarate release of a calcium α-ketoglutarate composition formulated in the absence of any controlled-release matrix. In some embodiments, the rate of calcium α-ketoglutarate release provided by the composition does not exceed 50% of the rate of calcium α-ketoglutarate release of a calcium α-ketoglutarate composition formulated in the absence of any controlled-release matrix. In some embodiments, the rate of calcium α-ketoglutarate release provided by the composition does not exceed 40% of the rate of calcium α-ketoglutarate release of a calcium α-ketoglutarate composition formulated in the absence of any controlled-release matrix. In some embodiments, the rate of calcium α-ketoglutarate release provided by the composition does not exceed 30% of the rate of calcium α-ketoglutarate release of a calcium α-ketoglutarate composition formulated in the absence of any controlled-release matrix. In some embodiments, the rate of calcium α-ketoglutarate release provided by the composition does not exceed 20% of the rate of calcium α-ketoglutarate release of a calcium α-ketoglutarate composition formulated in the absence of any controlled-release matrix. In some embodiments, the rate of calcium α-ketoglutarate release provided by the composition does not exceed 10% of the rate of calcium α-ketoglutarate release of a calcium α-ketoglutarate composition formulated in the absence of any controlled-release matrix. In some embodiments, the rate of calcium α-ketoglutarate release provided by the composition does not exceed 5% of the rate of calcium α-ketoglutarate release of a calcium α-ketoglutarate composition formulated in the absence of any controlled-release matrix.

[0085] Amount of calcium α-ketoglutarate

[0086] In some embodiments, the amount of calcium α-ketoglutarate is 15% to 85% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is 15% to 75% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is 30% to 70% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is 40% to 70% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is 30% to 65% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is 40% to 65% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is 30% to 60% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is 40% to 60% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is 45% to 55% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is 45% to 52% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is 46% to 53% by total weight of the composition.

[0087] In some embodiments, the amount of calcium α-ketoglutarate in the composition corresponds to about 10% w / w to about 75% w / w by total weight of the composition. In other embodiments, the amount of calcium α-ketoglutarate corresponds to about 10% w / w, about 15% w / w, about 18% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, about 30% w / w, about 31% w / w, about 32% w / w, about 33% w / w, about 34% w / w, about 35% w / w, about 36% w / w, about 37% w / w, about 38% w / w, about 39% w / w, about 40% w / w, about 41% w / w, about 42% w / w, about 43% w / w, about 44% w / w, about 45% w / w, about 46% w / w, about 47% w / w, about 48% w / w, about 49% w / w, about 50% w / w, about 51% w / w, about 52% w / w, about 53% w / w, about 54% w / w, about 55% w / w, about 56% w / w, about 57% w / w, about 58% w / w, about 59% w / w, about 60% w / w, about 61% w / w, about 62% w / w, about 63w / w, about 64% w / w, about 65% w / w, about 66% w / w, about 67% w / w, about 68% w / w, about 69% w / w, about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w or 75% w / w by total weight of the composition.

[0088] In some embodiments, the amount of calcium α-ketoglutarate is about 30%, 35%, 40%, 45%, 50%, 55%, 60% or 65% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is about 30% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is about 35% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is about 40% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is about 45% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is about 50% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is about 55% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is about 60% by total weight of the composition. In some embodiments, the amount of calcium α-ketoglutarate is about 65% by total weight of the composition.

[0089] Controlled-release matrix

[0090] In some embodiments, the controlled-release matrix comprises hydroxypropyl methylcellulose (HPMC). In some embodiments, the HPMC is selected from HPMC having a number average molecular weight of 22,000 - 30,000, 68,000 - 95,000, 115,000 - 150,000, 220,000 - 300,000, and combinations thereof. In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight between 68,000 - 95,000. In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight between 115,000 - 150,000. In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight between 65,000 to 102,000 and 103,000 to 156,000. In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight between 68,000 - 95,000 and 115,000 - 150,000. In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight between 77,000 to 95,000 and 109,000 to 128,000.

[0091] In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight between 18,000 and 44,000. In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight of at least 18,000. In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight of at most 44,000. In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight between 18,000 and 20,000, 18,000 and 23,000, 18,000 and 27,000, 18,000 and 30,000, 18,000 and 33,000, 18,000 and 36,000, 18,000 and 39,000, 18,000 and 41,000, 18,000 and 44,000, 20,000 and 23,000, 20,000 and 27,000, 20,000 and 30,000, 20,000 and 33,000, 20,000 and 36,000, 20,000 and 39,000, 20,000 and 41,000, 20,000 and 44,000, 23,000 and 27,000, 23,000 and 30,000, 23,000 and 33,000, 23,000 and 36,000, 23,000 and 39,000, 23,000 and 41,000, 23,000 and 44,000, 27,000 and 30,000, 27,000 and 33,000, 27,000 and 36,000, 27,000 and 39,000, 27,000 and 41,000, 27,000 and 44,000, 30,000 and 33,000, 30,000 and 36,000, 30,000 and 39,000, 30,000 and 41,000, 30,000 and 44,000, 33,000 and 36,000, 33,000 and 39,000, 33,000 and 41,000, 33,000 and 44,000, 36,000 and 39,000, 36,000 and 41,000, 36,000 and 44,000, 39,000 and 41,000, 39,000 and 44,000, or 41,000 and 44,000. In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight of 18,000, 20,000, 23,000, 27,000, 30,000, 33,000, 36,000, 39,000, 41,000 or 44,000.

[0092] In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight between 65,000 and 102,000. In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight of at least 65,000. In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight of at most 102,000.In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight between 65,000 and 68,000, 65,000 and 71,000, 65,000 and 74,000, 65,000 and 77,000, 65,000 and 80,000, 65,000 and 83,000, 65,000 and 87,000, 65,000 and 91,000, 65,000 and 95,000, 65,000 and 99,000, 65,000 and 102,000, 68,000 and 71,000, 68,000 and 74,000, 68,000 and 77,000, 68,000 and 80,000, 68,000 and 83,000, 68,000 and 87,000, 68,000 and 91,000, 68,000 and 95,000, 68,000 and 99,000, 68,000 and 102,000, 71,000 and 74,000, 71,000 and 77,000, 71,000 and 80,000, 71,000 and 83,000, 71,000 and 87,000, 71,000 and 91,000, 71,000 and 95,000, 71,000 and 99,000, 71,000 and 102,000, 74,000 and 77,000, 74,000 and 80,000, 74,000 and 83,000, 74,000 and 87,000, 74,000 and 91,000, 74,000 and 95,000, 74,000 and 99,000, 74,000 and 102,000, 77,000 and 80,000, 77,000 and 83,000, 77,000 and 87,000, 77,000 and 91,000, 77,000 and 95,000, 77,000 and 99,000, 77,000 and 102,000, 80,000 and 83,000, 80,000 and 87,000, 80,000 and 91,000, 80,000 and 95,000, 80,000 and 99,000, 80,000 and 102,000, 83,000 and 87,000, 83,000 and 91,000, 83,000 and 95,000, 83,000 and 99,000, 83,000 and 102,000, 87,000 and 91,000, 87,000 and 95,000, 87,000 and 99,000, 87,000 and 102,000, 91,000 and 95,000, 91,000 and 99,000, 91,000 and 102,000, 95,000 and 99,000, 95,000 and 102,000, or 99,000 and 102,000.In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight between 65,000, 68,000, 71,000, 74,000, 77,000, 80,000, 83,000, 87,000, 91,000, 95,000, 99,000 or 102,000.

[0093] In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight between 103,000 and 156,000. In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight of at least 103,000. In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight of at most 156,000. In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight between 103,000 and 109,000, 103,000 and 115,000, 103,000 and 118,000, 103,000 and 123,000, 103,000 and 128,000, 103,000 and 133,000, 103,000 and 138,000, 103,000 and 142,000, 103,000 and 146,000, 103,000 and 150,000, 103,000 and 156,000, 109,000 and 115,000, 109,000 and 118,000, 109,000 and 123,000, 109,000 and 128,000, 109,000 and 133,000, 109,000 and 138,000, 109,000 and 142,000, 109,000 and 146,000, 109,000 and 150,000, 109,000 and 156,000, 115,000 and 118,000, 115,000 and 123,000, 115,000 and 128,000, 115,000 and 133,000, 115,000 and 138,000, 115,000 and 142,000, 115,000 and 146,000, 115,000 and 150,000, 115,000 and 156,000, 118,000 and 123,000, 118,000 and 128,000, 118,000 and 133,000, 118,000 and 138,000, 118,000 and 142,000, 118,000 and 146,000, 118,000 and 150,000, 118,000 and 156,000, 123,000 and 128,000, 123,000 and 133,000, 123,000 and 138,000, 123,000 and 142,000, 123,000 and 146,000, 123,000 and 150,000, 123,000 and 156,000, 128,000 and 133,000, 128,000 and 138,000, 128,000 and 142,000, 128,000 and 146,000, 128,000 and 150,000, 128,000 and 156,000, 133,000 and 138,000, 133,000 and 142,000, 133,HPMC between 0 and 146,000, 133,000 and 150,000, 133,000 and 156,000, 138,000 and 142,000, 138,000 and 146,000, 138,000 and 150,000, 138,000 and 156,000, 142,000 and 146,000, 142,000 and 150,000, 142,000 and 156,000, 146,000 and 150,000, 146,000 and 156,000, or 150,000 and 156,000. In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight between 103,000, 109,000, 115,000, 118,000, 123,000, 128,000, 133,000, 138,000, 142,000, 146,000, 150,000 or 156,000.,

[0094] In some embodiments, the controlled-release matrix comprises HPMC having a number-average molecular weight between 170,000 and 320,000. In some embodiments, the controlled-release matrix comprises HPMC having a number-average molecular weight of at least 170,000. In some embodiments, the controlled-release matrix comprises HPMC having a number-average molecular weight of at most 320,000. In some embodiments, the controlled-release matrix comprises HPMC having a number-average molecular weight between 170,000 and 180,000, between 170,000 and 190,000, between 170,000 and 200,000, between 170,000 and 210,000, between 170,000 and 220,000, between 170,000 and 230,000, between 170,000 and 240,000, between 170,000 and 260,000, between 170,000 and 280,000, between 170,000 and 300,000, between 170,000 and 320,000, between 180,000 and 190,000, between 180,000 and 200,000, between 180,000 and 210,000, between 180,000 and 220,000, between 180,000 and 230,000, between 180,000 and 240,000, between 180,000 and 260,000, between 180,000 and 280,000, between 180,000 and 300,000, between 180,000 and 320,000, between 190,000 and 200,000, between 190,000 and 210,000, between 190,000 and 220,000, between 190,000 and 230,000, between 190,000 and 240,000, between 190,000 and 260,000, between 190,000 and 280,000, between 190,000 and 300,000, between 190,000 and 320,000, between 200,000 and 210,000, between 200,000 and 220,000, between 200,000 and 230,000, between 200,000 and 240,000, between 200,000 and 260,000, between 200,000 and 280,000, between 200,000 and 300,000, between 200,000 and 320,000, between 210,000 and 220,000, between 210,000 and 230,000, between 210,000 and 240,000, between 210,000 and 260,000, between 210,000 and 280,000, between 210,000 and 300,000, between 210,000 and 320,000, between 220,000 and 230,000, between 220,000 and 240,000, between 220,000 and 260,000, between 220,000 and 280,000, between 220,000 and 300,000, between 220,000 and 320,000, between 230,000 and 240,000, between 230,000 and 260,000, between 230,HPMC between 0 and 280,000, 230,000 and 300,000, 230,000 and 320,000, 240,000 and 260,000, 240,000 and 280,000, 240,000 and 300,000, 240,000 and 320,000, 260,000 and 280,000, 260,000 and 300,000, 260,000 and 320,000, 280,000 and 300,000, 280,000 and 320,000, or 300,000 and 320,000. In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight between 170,000, 180,000, 190,000, 200,000, 210,000, 220,000, 230,000, 240,000, 260,000, 280,000, 300,000 or 320,000.,

[0095] Release rate

[0096] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 0.5 and 2 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition does not exceed 30%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0097] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 0.5 and 2 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition does not exceed 25%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0098] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 0.5 and 1.5 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition does not exceed 25%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0099] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 0.5 and 1.5 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition does not exceed 20%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0100] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 1 hour, the release rate of calcium α-ketoglutarate provided by the composition is not more than 30%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0101] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 1 hour, the release rate of calcium α-ketoglutarate provided by the composition is not more than 25%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0102] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 1 hour, the release rate of calcium α-ketoglutarate provided by the composition is not more than 20%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0103] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 1 hour, the release rate of calcium α-ketoglutarate provided by the composition is not more than 19%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0104] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 1 hour, the release rate of calcium α-ketoglutarate provided by the composition is not more than 18%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0105] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 1 hour, the release rate of calcium α-ketoglutarate provided by the composition is not more than 17%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0106] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 1 hour, the release rate of calcium α-ketoglutarate provided by the composition is not more than 16%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0107] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 1 hour, the release rate of calcium α-ketoglutarate provided by the composition is not more than 15%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0108] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at a time between 4 and 8 hours, the release rate of calcium α-ketoglutarate provided by the composition is not more than 60%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0109] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at a time between 4 and 6 hours, the release rate of calcium α-ketoglutarate provided by the composition is not more than 60%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0110] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 8 hours, the release rate of calcium α-ketoglutarate provided by the composition is not more than 60%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0111] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 7 hours, the release rate of calcium α-ketoglutarate provided by the composition is not more than 60%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0112] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 6 hours, the release rate of calcium α-ketoglutarate provided by the composition is not more than 60%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0113] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 5 hours, the release rate of calcium α-ketoglutarate provided by the composition is not more than 60%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0114] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 5 hours, the release rate of calcium α-ketoglutarate provided by the composition is not more than 55%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0115] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 5 hours, the release rate of calcium α-ketoglutarate provided by the composition is not more than 50%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0116] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 4 hours, the release rate of calcium α-ketoglutarate provided by the composition is not more than 50%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0117] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 4 hours, the release rate of calcium α-ketoglutarate provided by the composition is not more than 45%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0118] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 4 hours, the release rate of calcium α-ketoglutarate provided by the composition is not more than 40%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0119] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 9 and 11 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 75%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0120] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 9 and 10 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 75%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0121] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 10 and 11 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 75%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0122] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at 9 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 75%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0123] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at 10 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 75%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0124] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at 11 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 75%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0125] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 11 and 15 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 90%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0126] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 11 and 14 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 90%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0127] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 11 and 13 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 90%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37 °C.

[0128] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 11 and 12 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 90%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0129] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 12 and 15 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 90%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0130] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 12 and 14 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 90%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0131] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at a time between 12 and 13 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 90%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0132] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at 11 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 90%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0133] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at 12 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 90%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0134] In some embodiments, as measured by a paddle apparatus having a basket rotating at 75 rpm, at 13 hours in the dissolution medium, the release rate of calcium α-ketoglutarate provided by the composition is not less than 90%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0135] In some embodiments, as measured by paddle apparatus having a basket rotating at 75 rpm, in the dissolution medium at 14 hours, the composition provides a release rate of calcium α-ketoglutarate of not less than 90%, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0136] In some embodiments, the composition comprises one or more excipients.

[0137] In some embodiments, the excipients are selected from the group consisting of diluents, fillers, disintegrants, lubricants, binders, suspending agents, and combinations thereof.

[0138] In some embodiments, the excipients are selected from the group consisting of diluents, fillers, disintegrants, lubricants, and combinations thereof.

[0139] In some embodiments, the composition comprises a first diluent. In some embodiments, the amount of the first diluent is 11% to 29% by total weight of the composition. In some embodiments, the amount of the first diluent is at least 11% by total weight of the composition. In some embodiments, the amount of the first diluent is at most 29% by total weight of the composition. In some embodiments, the amount of the first diluent is 11% to 14%, 11% to 17%, 11% to 19%, 11% to 20%, 11% to 21%, 11% to 23%, 11% to 25%, 11% to 27%, 11% to 29%, 14% to 17%, 14% to 19%, 14% to 20%, 14% to 21%, 14% to 23%, 14% to 25%, 14% to 27%, 14% to 29%, 17% to 19%, 17% to 20%, 17% to 21%, 17% to 23%, 17% to 25%, 17% to 27%, 17% to 29%, 19% to 20%, 19% to 21%, 19% to 23%, 19% to 25%, 19% to 27%, 19% to 29%, 20% to 21%, 20% to 23%, 20% to 25%, 20% to 27%, 20% to 29%, 21% to 23%, 21% to 25%, 21% to 27%, 21% to 29%, 23% to 25%, 23% to 27%, 23% to 29%, 25% to 27%, 25% to 29%, or 27% to 29% by total weight of the composition. In some embodiments, the amount of the first diluent is about 11%, about 14%, about 17%, about 19%, about 20%, about 21%, about 23%, about 25%, about 27%, or about 29% by total weight of the composition.

[0140] In some embodiments, the first diluent is microcrystalline cellulose. In some embodiments, the amount of microcrystalline cellulose is from 11% to 29% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is from 14% to 27% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is from 17% to 23% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is from 17% to 22% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is from 17% to 20% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is at least 11% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is at most 29% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is from 11% to 14%, 11% to 17%, 11% to 19%, 11% to 20%, 11% to 21%, 11% to 23%, 11% to 25%, 11% to 27%, 11% to 29%, 14% to 17%, 14% to 19%, 14% to 20%, 14% to 21%, 14% to 23%, 14% to 25%, 14% to 27%, 14% to 29%, 17% to 19%, 17% to 20%, 17% to 21%, 17% to 23%, 17% to 25%, 17% to 27%, 17% to 29%, 19% to 20%, 19% to 21%, 19% to 23%, 19% to 25%, 19% to 27%, 19% to 29%, 20% to 21%, 20% to 23%, 20% to 25%, 20% to 27%, 20% to 29%, 21% to 23%, 21% to 25%, 21% to 27%, 21% to 29%, 23% to 25%, 23% to 27%, 23% to 29%, 25% to 27%, 25% to 29%, or 27% to 29% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 11% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 14% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 17% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 19% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 20% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 21% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 23% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 25% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 27% by total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 29% by total weight of the composition.

[0141] In some embodiments, the composition comprises a second diluent. In some embodiments, the amount of the second diluent is from 4% to 19% by total weight of the composition. In some embodiments, the amount of the second diluent is at least 4% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is at most 19% by total weight of the composition. In some embodiments, the amount of the second diluent is from 4% to 6%, from 4% to 8%, from 4% to 10%, from 4% to 11%, from 4% to 12%, from 4% to 13%, from 4% to 14%, from 4% to 15%, from 4% to 17%, from 4% to 19%, from 6% to 8%, from 6% to 10%, from 6% to 11%, from 6% to 12%, from 6% to 13%, from 6% to 14%, from 6% to 15%, from 6% to 17%, from 6% to 19%, from 8% to 10%, from 8% to 11%, from 8% to 12%, from 8% to 13%, from 8% to 14%, from 8% to 15%, from 8% to 17%, from 8% to 19%, from 10% to 11%, from 10% to 12%, from 10% to 13%, from 10% to 14%, from 10% to 15%, from 10% to 17%, from 10% to 19%, from 11% to 12%, from 11% to 13%, from 11% to 14%, from 11% to 15%, from 11% to 17%, from 11% to 19%, from 12% to 13%, from 12% to 14%, from 12% to 15%, from 12% to 17%, from 12% to 19%, from 13% to 14%, from 13% to 15%, from 13% to 17%, from 13% to 19%, from 14% to 15%, from 14% to 17%, from 14% to 19%, from 15% to 17%, from 15% to 19% or from 17% to 19% by total weight of the composition. In some embodiments, the amount of the second diluent is about 4%, about 6%, about 8%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 17% or about 19% by total weight of the composition.

[0142] In some embodiments, the second diluent is lactose monohydrate. In some embodiments, the amount of lactose monohydrate is from 4% to 19% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is from 6% to 19% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is from 8% to 17% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is from 10% to 15% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is from 11% to 14% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is at least 4% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is at most 19% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is from 4% to 6%, 4% to 8%, 4% to 10%, 4% to 11%, 4% to 12%, 4% to 13%, 4% to 14%, 4% to 15%, 4% to 17%, 4% to 19%, 6% to 8%, 6% to 10%, 6% to 11%, 6% to 12%, 6% to 13%, 6% to 14%, 6% to 15%, 6% to 17%, 6% to 19%, 8% to 10%, 8% to 11%, 8% to 12%, 8% to 13%, 8% to 14%, 8% to 15%, 8% to 17%, 8% to 19%, 10% to 11%, 10% to 12%, 10% to 13%, 10% to 14%, 10% to 15%, 10% to 17%, 10% to 19%, 11% to 12%, 11% to 13%, 11% to 14%, 11% to 15%, 11% to 17%, 11% to 19%, 12% to 13%, 12% to 14%, 12% to 15%, 12% to 17%, 12% to 19%, 13% to 14%, 13% to 15%, 13% to 17%, 13% to 19%, 14% to 15%, 14% to 17%, 14% to 19%, 15% to 17%, 15% to 19% or 17% to 19% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 4% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 6% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 8% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 10% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 11% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 12% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 13% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 14% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 15% by total weight of the composition.In some embodiments, the amount of lactose monohydrate is about 17% by total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 19% by total weight of the composition.

[0143] In some embodiments, the composition comprises a lubricant. In some embodiments, the amount of the lubricant is 1% to 5% by total weight of the composition. In some embodiments, the amount of the lubricant is at least 1% by total weight of the composition. In some embodiments, the amount of the lubricant is at most 5% by total weight of the composition. In some embodiments, the amount of the lubricant is 1% to 2%, 1% to 3%, 1% to 4%, 1% to 5%, 2% to 3%, 2% to 4%, 2% to 5%, 3% to 4%, 3% to 5% or 4% to 5% by total weight of the composition. In some embodiments, the amount of the lubricant is 1%, 2%, 3%, 4% or 5% by total weight of the composition.

[0144] In some embodiments, the lubricant is magnesium stearate. In some embodiments, the amount of magnesium stearate is 1% to 5% by total weight of the composition. In some embodiments, the amount of magnesium stearate is 1% to 3% by total weight of the composition. In some embodiments, the amount of magnesium stearate is 2% to 4% by total weight of the composition. In some embodiments, the amount of magnesium stearate is at least 1% by total weight of the composition. In some embodiments, the amount of magnesium stearate is at most 5% by total weight of the composition. In some embodiments, the amount of magnesium stearate is 1% to 2%, 1% to 3%, 1% to 4%, 1% to 5%, 2% to 3%, 2% to 4%, 2% to 5%, 3% to 4%, 3% to 5% or 4% to 5% by total weight of the composition. In some embodiments, the amount of magnesium stearate is 1%, 2%, 3%, 4% or 5% by total weight of the composition.

[0145] In some embodiments, the amount of magnesium stearate is about 1% by total weight of the composition. In some embodiments, the amount of magnesium stearate is about 2% by total weight of the composition. In some embodiments, the amount of magnesium stearate is about 3% by total weight of the composition. In some embodiments, the amount of magnesium stearate is about 4% by total weight of the composition. In some embodiments, the amount of magnesium stearate is about 5% by total weight of the composition.

[0146] In some embodiments, the composition comprises a disintegrant. In some embodiments, the amount of the disintegrant is from 1% to 5% by total weight of the composition. In some embodiments, the amount of the disintegrant is at least 1% by total weight of the composition. In some embodiments, the amount of the disintegrant is at most 5% by total weight of the composition. In some embodiments, the amount of the disintegrant is from 1% to 2%, from 1% to 3%, from 1% to 4%, from 1% to 5%, from 2% to 3%, from 2% to 4%, from 2% to 5%, from 3% to 4%, from 3% to 5%, or from 4% to 5% by total weight of the composition. In some embodiments, the amount of the disintegrant is 1%, 2%, 3%, 4%, or 5% by total weight of the composition.

[0147] In some embodiments, the disintegrant is silica. In some embodiments, the amount of silica is from 1% to 5% by total weight of the composition. In some embodiments, the amount of silica is from 1% to 3% by total weight of the composition. In some embodiments, the amount of silica is from 2% to 4% by total weight of the composition. In some embodiments, the amount of silica is at least 1% by total weight of the composition. In some embodiments, the amount of silica is at most 5% by total weight of the composition. In some embodiments, the amount of silica is from 1% to 2%, from 1% to 3%, from 1% to 4%, from 1% to 5%, from 2% to 3%, from 2% to 4%, from 2% to 5%, from 3% to 4%, from 3% to 5%, or from 4% to 5% by total weight of the composition.

[0148] In some embodiments, the amount of silica is about 1% by total weight of the composition. In some embodiments, the amount of silica is about 2% by total weight of the composition. In some embodiments, the amount of silica is about 3% by total weight of the composition. In some embodiments, the amount of silica is about 4% by total weight of the composition. In some embodiments, the amount of silica is about 5% by total weight of the composition.

[0149] Composition of α-ketoglutaric acid compounds

[0150] In another aspect, the present disclosure describes a composition comprising calcium α-ketoglutarate and one or more agents selected from the group consisting of surfactants, preservatives, flavoring agents, vitamins, antioxidants, sweeteners, and combinations thereof.

[0151] In some embodiments, the amount of calcium α-ketoglutarate is from 50 mg to 5000 mg. In some embodiments, the amount of calcium α-ketoglutarate is from 100 mg to 2000 mg. In some embodiments, the amount of calcium α-ketoglutarate is about 250 mg. In some embodiments, the amount of calcium α-ketoglutarate is about 500 mg. In some embodiments, the amount of calcium α-ketoglutarate is about 525 mg. In some embodiments, the amount of calcium α-ketoglutarate is about 550 mg. In some embodiments, the amount of calcium α-ketoglutarate is about 750 mg.

[0152] In some embodiments, calcium α-ketoglutarate is calcium α-ketoglutarate monohydrate.

[0153] In some embodiments, the composition comprises a vitamin. In some embodiments, the vitamin is vitamin A. In some embodiments, the amount of vitamin A is from 100 mcg to 3000 mcg; from 200 mcg to 1000 mcg; about 250 mcg; about 450 mcg; or about 650 mcg. In some embodiments, vitamin A is retinyl palmitate.

[0154] In some embodiments, the vitamin is vitamin D. In some embodiments, the amount of vitamin D is from 50 IU to 3000 IU; from 200 IU to 2000 IU; or about 250 IU. In some embodiments, the amount of vitamin D is about 500 IU. In some embodiments, the amount of vitamin D is about 750 IU. In some embodiments, vitamin D is cholecalciferol.

[0155] In some embodiments, the composition further comprises a sweetener. In some embodiments, the sweetener is isomaltitol.

[0156] In some embodiments, the composition further comprises a wax. In some embodiments, the wax is carnauba wax and / or rice bran wax.

[0157] In some embodiments, the composition further comprises one or more excipients. In some embodiments, the excipients are selected from the group consisting of solubilizers, diluents, fillers, disintegrants, lubricants, glidants, binders, suspending agents, and combinations thereof. In some embodiments, the excipients are selected from the group consisting of solubilizers, diluents, fillers, disintegrants, lubricants, glidants, and combinations thereof.

[0158] In some embodiments, the composition further comprises a first lubricant. In some embodiments, the first lubricant is stearic acid. In some embodiments, the composition comprises a second lubricant. In some embodiments, the second lubricant is magnesium stearate. In some embodiments, the composition comprises a glidant. In some embodiments, the glidant is silica.

[0159] In another aspect, the present disclosure also describes a composition comprising 500 mg of calcium α-ketoglutarate monohydrate; 450 mcg of retinyl palmitate; and further comprising isomalt, plant wax (carnauba wax and / or rice bran wax), stearic acid, magnesium stearate, and silica.

[0160] In another aspect, the present disclosure also describes a composition comprising 500 mg of calcium α-ketoglutarate monohydrate; 12.5 mcg (500 IU) of cholecalciferol; and further comprising isomalt, plant wax (carnauba wax and / or rice bran wax), stearic acid, magnesium stearate, and silica.

[0161] Controlled-release matrix formulation

[0162] In certain embodiments, the compositions of calcium α-ketoglutarate described herein comprise a controlled-release matrix. Bioactive agents can be released from the controlled-release matrix by a number of mechanisms. Two mechanisms include diffusion and / or degradation. Diffusion occurs when the bioactive agent is released through pores in the polymeric matrix or by passing between the polymer chains of the matrix. In a diffusion system, the bioactive agent may be dispersed throughout the matrix or confined to a reservoir adjacent to or within the matrix. In a reservoir system, a reservoir of the bioactive agent (such as a solid drug, a dilute solution, or a concentrated drug solution) within the polymeric matrix is surrounded by a controlled-release material through which the bioactive agent can diffuse. In a degradable system, the bioactive agent is released as the matrix degrades in vivo. The bioactive agent may also be released by a combination of these two mechanisms. In some embodiments of the controlled-release matrix described herein, the release of the bioactive agent is driven by a combination of both diffusion and degradation. The release rate can be controlled by changing the ratio of the drug to the polymer (e.g., higher drug concentrations tend to result in faster release rates), changing the chemical nature of the polymeric matrix (e.g., the incorporation of polymers with a Tg less than about 40 °C or less than about 0 °C tends to result in faster elution rates than polymers with a Tg greater than 40 °C; polymers that absorb water tend to elute the drug faster than hydrophobic polymers that do not absorb water). These variables can be controlled by selecting the materials used in the manufacturing process.

[0163] In some embodiments, the controlled release matrix is configured to release the bioactive agent as set forth above. In some embodiments, the controlled release matrix is configured to release at least about 40% and at most about 60% or at least 50% of the bioactive agent within 12 hours after administration. In some embodiments, the controlled release matrix is configured to release at least about 40% and at most about 60% or at least 50% of the bioactive agent within 24 hours after administration. In another embodiment, the controlled release matrix is configured to release at least about 80% or at most about 100% or at least 90% of the bioactive agent within 7 days after administration.

[0164] In some embodiments, the controlled release matrix is biodegradable. In some embodiments, the controlled release matrix comprises a biodegradable polyester. Examples of biodegradable polyesters include, but are not limited to: polycaprolactone (PCL), polylactic acid (PLA), polyglycolide (PGA), and copolymers thereof, such as poly(lactic-co-glycolic) polymer (PLGA) and poly(glycolide-co-caprolactone) (PGC). Polycaprolactone (PCL) refers to a biodegradable polyester prepared by ring-opening polymerization of ε-caprolactone using a catalyst such as stannous octoate. Polycaprolactone has a melting point of about 60 °C and degrades under physiological conditions by hydrolysis of its ester linkages.

[0165] Polylactic acid (PLA) is a biodegradable thermoplastic polyester that can be produced by bacterial fermentation of renewable resources such as corn, starch, or sugarcane and has a melting temperature between about 173 °C and about 178 °C.

[0166] Polyglycolide (PGA) is a biodegradable thermoplastic polyester prepared from glycolic acid by polycondensation or ring-opening polymerization. Its melting point is between about 225 °C and about 230 °C.

[0167] Poly(lactic-co-glycolic acid) polymer (PLGA) refers to a biodegradable copolymer of lactic acid and glycolic acid formed by the random ring-opening copolymerization of glycolic acid and lactic acid monomers. During the polymerization process, the monomer units are linked together by ester bonds, resulting in an aliphatic polyester. PLGA is amorphous and has a glass transition temperature between approximately 40°C and 60°C. Generally, PLGA copolymers have a weight-average molecular weight between approximately 1000 daltons and approximately 50,000 daltons or between approximately 5000 daltons and 25,000 daltons. The ratio of lactic acid to glycolic acid can vary. Typically, an increase in the amount of lactic acid results in slower polymer degradation. An increase in glycolic acid results in faster polymer degradation. In addition, an increase in glycolic acid tends to lower the glass transition temperature (Tg) and the penetration of water into the polymer, which leads to faster release of the compound. Generally, the ratio of lactic acid to glycolic acid is between approximately 100:0 and approximately 25:75 or between approximately 60:40 and 40:60 or approximately 50:50.

[0168] Other suitable biodegradable polymers include, but are not limited to, poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), and poly(butylene succinate) (PBS), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxybutyrate) (PHB), and poly(butylene succinate) (PBS).

[0169] In some embodiments, the polymeric material or polymer is bio-stable. Examples of bio-stable polymers include, but are not limited to, polyurethanes, silicone rubbers, styrene-isobutylene-styrene block copolymers, ether-ester block copolymers (e.g., 1500-40D from RTP Co.), and vinyl materials, including, but not limited to, poly(ethylene-co-vinyl acetate) (PEVA).

[0170] In some embodiments, the controlled release matrix comprises an elastomeric polymeric material, which comprises a copolymer having an elastic (or "soft") component and a non-elastic (or "hard") component. In another embodiment, the elastomeric polymeric material comprises a polymeric blend having an elastic component and a non-elastic component.

[0171] In some embodiments, the compliant polymer or polymeric material is thermoplastic. As used herein, the term "thermoplastic" refers to a polymer or polymeric material that can be softened by heating, hardened by cooling, and then softened again by heating over and over. Generally, thermoplastic materials are uncrosslinked. However, in another embodiment, the compliant polymer or polymeric material can be crosslinked.

[0172] A bioactive agent can be incorporated into a controlled release matrix of any of a variety of techniques known to those of skill in the art. In one embodiment, the bioactive agent is dispersed throughout the controlled release matrix. Techniques for preparing the controlled release matrix include, but are not limited to, melt extrusion processes, injection molding, or spray casting.

[0173] In a melt extrusion process, a mixture comprising a polymeric material and a bioactive agent is combined in an extruder, heated to a temperature at which the polymeric material melts, and then discharged through an orifice having a desired cross-sectional shape. The extruded material is collected under controlled conditions (e.g., speed, temperature, and humidity) to obtain a product having the desired dimensions. In one embodiment, the mass flow rate of the extrudate and the collection rate of the final extruded form can be controlled to obtain the desired physical dimensions. For example, if the final extruded form is a film, the collection rate of the film may be increased relative to the mass flow rate of the extrudate to reduce the film thickness, and vice versa, to increase the film thickness. The extrudate is discharged through the orifice in a molten state, causing the extrudate to elongate to its final dimensions. The extrudate is then cooled by exposure to ambient conditions, a cooling liquid or gas bath, or a temperature-controlled surface (such as a cooling roll) to solidify the extrudate. In one embodiment, the melt extrusion process is used to form a film. In an alternative embodiment, the melt extrusion process is used to form pellets or beads, which can then be molded into a desired film or collar configuration. Some advantages of the melt extrusion process include: no organic solvents, and high throughput, continuous manufacturing. Generally, the processing temperature is sufficient to melt the polymeric material without adversely affecting the bioactivity of the bioactive agent. Generally, the processing temperature is at least about 80°C or about 100°C, and less than about 180°C, less than 160°C, or between about 110°C and about 150°C. In some embodiments, the specific temperature depends on the melting and degradation temperatures of the polymeric material and the bioactive agent. Additionally, melt processing provides the ability for continuous operation, the ability to control operating parameters, and the ability to scale up manufacturing.

[0174] In an alternative embodiment, an injection molding process is used. In an injection molding process, a mixture comprising a polymeric material and a bioactive agent is fed into a container (where the mixture is heated to a temperature sufficient to melt the polymeric material), and then forced into a mold cavity (where the mixture is cooled and hardened into the configuration of the mold cavity). The conditions (e.g., temperature and pressure) will depend on the material being molded. In one embodiment, the injection molding process is used to form a film or a collar.

[0175] In yet another embodiment, solvent casting techniques can be used. In a solvent casting process, a polymeric material and a bioactive agent are combined with a suitable solvent to form a polymer solution, which is then cast onto a substrate. The solvent is then removed, for example, by evaporation to form a film. In one embodiment, the solvent is removed under vacuum (e.g., between about 15 inches of mercury and about 28 inches of mercury, depending on the volatility of the solvent). In another embodiment, the solvent is removed at an elevated temperature (e.g., between about 30 °C and about 80 °C). In an alternative embodiment, the polymer solution is applied to the substrate by a spraying process. In a spraying process, the polymer solution is fed at a controlled rate to, for example, a nozzle and an ultrasonic nozzle by a positive displacement pump. The nozzle and the substrate are moved relative to each other at a controlled speed to achieve the desired coating thickness. The nozzle is mounted on a three-axis motion control system (x-y-z) that is capable of controlling the speed and position of the nozzle relative to the substrate. Additionally, if the substrate is a roll of film, it is traversed under the nozzle by a roll-to-roll unwind and rewind apparatus. The coating width is controlled by moving the nozzle along a specified path across the width of the substrate. Further, the height (z) of the nozzle above the substrate can be increased to obtain a wider coating width.

[0176] The solvent can be a solvent in which one or more components of the polymeric material form a true solution. The bioactive agent may be soluble in the solvent or form a dispersion throughout the solvent. Suitable solvents include, but are not limited to, alcohols (e.g., methanol, butanol, propanol, and isopropanol), alkanes (e.g., halogenated or unhalogenated alkanes such as hexane, cyclohexane, dichloromethane, and chloroform), amides (e.g., dimethylformamide), ethers (e.g., tetrahydrofuran (THF), dioxolane, and dioxane), ketones (e.g., methyl ethyl ketone, acetone), aromatic compounds (e.g., toluene and xylene), nitriles (e.g., acetonitrile), and esters (e.g., ethyl acetate). THF and chloroform have been found to be suitable solvents because of their excellent solubilizing ability for a wide variety of polymers and bioactive agents.

[0177] Excipients

[0178] In certain embodiments, the compositions of calcium α-ketoglutarate described herein contain excipients. In some embodiments, the compositions disclosed herein contain excipients such as suspending agents (e.g., methylcellulose), wetting agents (e.g., lecithin, lysolecithin, and / or long-chain fatty alcohols), as well as colorants, preservatives, flavoring agents, and the like.

[0179] The compositions disclosed herein can also be incorporated into foodstuffs (e.g., cream cheese, butter, salad dressings, or ice cream) to facilitate dissolution, administration, and / or compliance in certain patient populations.

[0180] The products for oral use can be obtained in the form of solid excipients, optionally grinding the resulting mixture, and processing the granular mixture (if necessary) after adding suitable auxiliaries to obtain tablets or dragee cores. Suitable excipients are especially fillers such as sugars (including lactose, sucrose, mannitol or sorbitol); flavoring components, cellulose products (such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP)). If necessary, disintegrants such as cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts such as sodium alginate can be added. The active compounds can also be formulated into sustained-release products.

[0181] The dragee cores may have a suitable coating. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablet or dragee coating for the identification or characterization of different combinations of active compound doses.

[0182] The products for oral use include push-fit capsules made of gelatin, and soft-sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). The push-fit capsules can contain a mixture of the active ingredient with a filler (such as lactose), a binder (such as starch) and / or a lubricant (such as talc or magnesium stearate) and optionally a stabilizer. In the soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers can be added. All compositions for oral administration should be in a dosage suitable for administration.

[0183] For injection, the compositions disclosed herein can be formulated in an aqueous solution, preferably in a physiologically compatible buffer such as Hank's solution, Ringer's solution or physiological saline buffer. Such compositions can also include one or more excipients, such as preservatives, solubilizers, fillers, lubricants, stabilizers, albumin, etc. The formulation methods are known in the art, for example, as disclosed in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, Pa. These compositions can also be formulated for transmucosal administration, buccal administration, for administration by inhalation, for parenteral administration, for transdermal administration and rectal administration.

[0184] In addition to the disclosed formulations, the compositions can also be formulated as depot products. Such long-acting formulations can be administered by implantation or transdermal delivery (e.g., subcutaneously or intramuscularly), intramuscular injection, or using a transdermal patch. Thus, for example, the compositions can be formulated with a suitable polymeric or hydrophobic material (e.g., formulated as an emulsion in an acceptable oil) or an ion exchange resin, or formulated as a slightly soluble derivative (e.g., formulated as a sparingly soluble salt).

[0185] In some embodiments, the formulations of the compositions disclosed herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast-dissolving formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multi-particle formulations (e.g., nanoparticle formulations), and immediate release / controlled release hybrid formulations.

[0186] In some embodiments, the formulations contain one or more carrier materials selected based on their compatibility with the compositions disclosed herein and the release profile characteristics of the desired dosage form. Compatible carrier materials include, but are not limited to, gum arabic, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan, glycerol monostearate, glycerol distearate, pregelatinized starch, and any combination thereof. See, e.g., The Science and Practice of Pharmacy, 19th ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins 1999).

[0187] In some examples, the formulation further comprises a pH adjuster or buffer, which includes acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris(hydroxymethyl)aminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are incorporated in amounts required to maintain the pH of the composition within an acceptable range.

[0188] In some examples, the formulation contains one or more salts in amounts required to bring the osmolality of the composition to an acceptable range. Such salts include salts having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0189] In some examples, the formulation contains a binder that is used to hold calcium α-ketoglutarate and the inactive ingredients together to form a viscous mixture. Suitable binders include, but are not limited to, carboxymethyl cellulose, methyl cellulose (e.g., ), hydroxypropyl methyl cellulose (e.g., hypromellose USP Pharmacoat-603, hypromellose acetate succinate (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., ), ethyl cellulose (e.g., ), and microcrystalline cellulose (e.g., ), microcrystalline dextrin, amylase, magnesium aluminum silicate, polygalacturonic acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars (such as sucrose (e.g., ), glucose, dextran, molasses, mannitol, sorbitol, xylitol (e.g., ), lactose, natural or synthetic gums (such as gum arabic, tragacanth, ghattigum, mucilage of isapol husks)), starch, polyvinylpyrrolidone (e.g., CL, CL, XL-10, and K-12), larch arabinogalactan, polyethylene glycol, wax, sodium alginate, and any combination thereof.

[0190] In some examples, the formulation further comprises a diluent for stabilizing calcium α-ketoglutarate, as they provide a more stable environment. Salts dissolved in a buffer solution (which also provides pH control or maintenance) are used as diluents in the art, including but not limited to phosphate buffered saline solutions. In certain examples, the diluent increases the volume of the composition to make the homogeneous blend for capsule filling more compressible or creates sufficient volume for the homogeneous blend for capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as calcium hydrogen phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugar (such as (Amstar)); mannitol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluent, confectioner's sugar; calcium sulfate monobasic monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, glucose binder; hydrolyzed cereal solids, amylase; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite and any combination thereof.

[0191] In some cases, the formulation contains a disintegration agent to facilitate the decomposition or disintegration of the substance. The term "disintegration" includes the dissolution and dispersion of the dosage form upon contact with gastrointestinal fluids. Examples of disintegrants include starches, such as natural starches, such as corn starch or potato starch; pregelatinized starches, such as National 1551 or or sodium starch glycolate, such as or celluloses, such as wood products; methylcrystalline cellulose, for example PH101, PH102, PH105, Pl 00, Ming and methylcellulose, cross-linked carboxymethylcellulose or cross-linked cellulose, such as sodium carboxymethylcellulose cross-linked cross-linked carboxymethylcellulose or cross-linked cross-linked carboxymethylcellulose; cross-linked starch, such as sodium starch glycolate; cross-linked polymers, such as cross-linked povidone; cross-linked polyvinylpyrrolidone; alginic acid compounds, such as alginic acid or salts of alginic acid, such as sodium alginate; clays, such as HV (magnesium aluminum silicate); gums such as agar, guar gum, locust bean gum, karaya gum, pectin, or tragacanth gum; sodium starch glycolate; bentonite; natural sponge; surfactant; resin such as cation exchange resin; citrus pulp, sodium dodecyl sulfate; combination of sodium dodecyl sulfate and starch; and any combination thereof.

[0192] In some examples, the formulation contains fillers such as lactose, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, glucose binder, dextran, starch, pregelatinized starch, hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol and any combination thereof.

[0193] Lubricants and glidants are also optionally included in the formulations disclosed herein to prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, hydrocarbons such as mineral oil or hydrogenated vegetable oils such as hydrogenated soybean oil Higher fatty acids and their alkali metal and alkaline earth metal salts (such as aluminum, calcium, magnesium, zinc), stearic acid, sodium stearate, glycerol, talc, wax Boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG-4000) or methoxypolyethylene glycol (such as Carbowax TM ), sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium dodecyl sulfate or sodium dodecyl sulfate, colloidal silica (such as Syloid TM , ), starch (such as corn starch), silicone oil, surfactant and any combination thereof.

[0194] Plasticizers include compounds used to soften microencapsulation materials or film coatings to make them less brittle. Suitable plasticizers include, for example, polyethylene glycol (such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800), stearic acid, propylene glycol, oleic acid, triethyl cellulose and triacetin. Plasticizers can also act as dispersants or wetting agents.

[0195] Solubilizers include compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrin, ethanol, n-butanol, isopropanol, cholesterol, bile salts, polyethylene glycol 200-600, glycogen, diethylene glycol monoethyl ether, propylene glycol, and dimethyl isosorbide and any combination thereof.

[0196] Stabilizers include compounds such as any antioxidants, buffers, acids, preservatives, and any combination thereof.

[0197] Suspending agents include compounds such as polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30), vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol (e.g., polyethylene glycol with a molecular weight of about 300 to about 6000 or about 3350 to about 4000 or about 7000 to about 5400), sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums (such as gum tragacanth and gum arabic, guar gum, xanthans (including xanthan gum)), sugars, celluloses (such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose), polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and any combination thereof.

[0198] Surfactants include compounds such as sodium lauryl sulfate, sodium doccusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, polaxomer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide (e.g., (BASF)) and any combination thereof. Additional surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers, such as octoxynol 10, octoxynol 40. Sometimes, surfactants are included to enhance physical stability or for other purposes.

[0199] The thickening agents include, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose acetate stearate, hypromellose phthalate, carbomer, polyvinyl alcohol, alginate, gum arabic, chitosan, and combinations thereof.

[0200] The wetting agents include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts, and any combination thereof.

[0201] An antifoaming agent is a chemical additive that reduces and hinders foam formation during the preparation of an orally administered liquid formulation. The terms antifoaming agent and defoamer are often used interchangeably. Common agents are insoluble oils, polydimethylsiloxane (such as dimethicone) and other silicones, certain alcohols, stearates, and ethylene glycols. This additive is used to prevent foam formation or to be added to break down already formed foam. The antifoaming agent reduces foaming that may occur during the preparation of an orally administered liquid formulation and cause coagulation of the aqueous dispersion. In certain embodiments, the calcium α-ketoglutarate composition described herein comprises an antifoaming agent. In some embodiments, the antifoaming agent is dimethicone.

[0202] In some embodiments, there is a significant overlap among the excipients used in the calcium α-ketoglutarate compositions, formulations, and dosage forms described herein. Accordingly, the additives listed above should be considered exemplary only and not limiting of the types of additives that may be included in the solid dosage forms of the compositions described herein.

[0203] Double-layer formulation

[0204] In some embodiments, the compositions described herein are formulated as double-layer formulations. In some examples, the double-layer formulations containing calcium α-ketoglutarate have enhanced bioavailability and a lower administration dose. In some embodiments, the double-layer formulation is an orally administered dosage form comprising an immediate-release top layer and a controlled-release core.

[0205] Controlled-release coating formulation

[0206] In some embodiments, at least one controlled-release coating surrounds the core of an oral dosage form. In certain embodiments, the controlled-release coating is a stable, controlled-release monolithic coating formed by a process that includes coating the core with a coating composition to form a coated core having an intermediate coating and curing the coated core to form the stable, controlled-release coating. In at least one embodiment, the coating composition comprises an aqueous dispersion of a neutral ester copolymer that contains no functional groups, polyethylene glycol having a melting point of at least 55 °C, and one or more second excipients. Curing is carried out at a temperature at least equal to or higher than the melting point of the polyethylene glycol. In at least one embodiment, the stable controlled-release coating comprises a neutral ester copolymer that contains no functional groups, polyethylene glycol having a melting point of at least 55 °C, and one or more second excipients.

[0207] The coating composition comprises an aqueous dispersion of a neutral ester copolymer that contains no functional groups. The aqueous dispersion of the neutral ester copolymer that contains no functional groups can be an ethyl acrylate and methyl methacrylate copolymer dispersion. Non-limiting examples of the ethyl acrylate and methyl methacrylate copolymer dispersion include a 30% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate (e.g. NE30D), a 40% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate (e.g. NE40D), NM30D, EMM30D, and combinations thereof. In at least one embodiment, the neutral ester copolymer that contains no functional groups for the controlled-release coating composition is NE30D, NE40D or a mixture thereof. In certain embodiments, a neutral ester copolymer that does not contain any functional groups can be present in an amount of about 1% to about 35% by weight of the coating composition, depending on the therapeutic active agent used and the desired controlled release profile. In certain embodiments, the neutral ester copolymer that does not contain any functional groups is present in an amount of about 20% to about 99.5% by weight of the dry coating weight. In other embodiments, the neutral ester copolymer that does not contain any functional groups is present in an amount of about 25% to about 60% by weight of the dry coating weight. In still other embodiments, the neutral ester copolymer that does not contain any functional groups is present in an amount of about 37% to about 50% by weight of the dry coating weight. In some embodiments, the neutral ester copolymer that does not contain any functional groups is present in an amount of about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48% and about 49% by weight of the dry coating weight. In certain embodiments, the neutral ester copolymer that does not contain any functional groups is present in the coating composition in an amount of about 0.4% to about 39.8% by weight of the tablet dry weight. In other embodiments, the amount is about 0.8% to about 24% by weight of the tablet dry weight. In some other embodiments, the neutral ester copolymer that does not contain any functional groups is present in the coating composition in an amount of about 2% to about 5.5% by weight of the tablet dry weight, such as about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4% by weight of the tablet dry weight.

[0208] In some embodiments, the controlled release dosage form does not swell in an unrestricted manner upon water absorption. In certain embodiments, the controlled release dosage form exhibits some swelling in a restricted manner upon water absorption. In certain embodiments, the controlled release coating restricts the swelling of the dosage form upon water absorption.

[0209] The coating composition further comprises polyethylene glycol having a melting point of at least about 55°C. The polyethylene glycol having a melting point of at least about 55°C can be polyethylene glycol having an average molecular weight in the range of about 4,000 Daltons to about 35,000 Daltons. Non-limiting examples of polyethylene glycol having a melting point of at least about 55°C that can be used with the coating composition include polyethylene glycol 4000, polyethylene glycol 4600, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 12000, polyethylene glycol 20000, polyethylene glycol 35000, and mixtures thereof. In certain embodiments, the polyethylene glycol is selected from the group consisting of polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 12000, and mixtures thereof. In at least one embodiment, the polyethylene glycol used in the coating composition is polyethylene glycol 8000. In certain embodiments, the polyethylene glycol can be present in an amount of about 0.1% to about 10% by weight of the coating composition. In certain embodiments, the polyethylene glycol can be present in an amount of about 0.5% to about 28% by dry weight of the coating. In other embodiments, the polyethylene glycol can be present in an amount of about 4% to about 17% by dry weight of the coating. In still other embodiments, the polyethylene glycol is present in an amount of about 7.2% to about 15.2% by dry weight of the coating, such as about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9%, about 9.1%, about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9%, about 10%, about 10.1%, about 10.2%, about 10.3%, about 10.4%, about 10.5%, about 10.6%, about 10.7%, about 10.8%, about 10.9%, about 11%, about 11.1%, about 11.2%, about 11.3%, about 11.4%, about 11.5%, about 11.6%, about 11.7%, about 11.8%, about 11.9%, about 12%, about 12.1%, about 12.2%, about 12.3%, about 12.4%, about 12.5%, about 12.6%, about 12.7%, about 12.8%, about 12.9%, about 13%, about 13.1%, about 13.2%, about 13.3%, about 13.4%, about 13.5%, about 13.6%, about 13.7%, about 13.8%, about 13.9%, about 14%, about 14.1%, about 14.2%, about 14.3%, about 14.4%, about 14.5%, about 14.6%, about 14.7%, about 14.8%, about 14.9%, about 15%, and about 15.1% by dry weight of the coating.In certain embodiments, polyethylene glycol may be present in the coating composition in an amount of from about 0.1% to about 11.2% by tablet dry weight. In other embodiments, polyethylene glycol may be present in the coating composition in an amount of from about 0.1% to about 8% by tablet dry weight. In some other embodiments, polyethylene glycol is present in the coating composition in an amount of from about 0.2% to about 2.8%, such as about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6% and about 2.7% by tablet dry weight. Other suitable polyethylene glycol derivatives having a melting point of at least about 55 °C may be, but are not limited to, poloxamer 188, poloxamer 338, poloxamer 407, polyethylene oxide, polyoxyethylene alkyl ether, polyoxyethylene stearate, and mixtures thereof.

[0210] In addition to the copolymer and polyethylene glycol, the coating composition further comprises one or more other excipients. Excipients may include, but are not limited to, anti-sticking agents, emulsifiers, defoaming agents, hydrophilic agents, flavoring agents, coloring agents, sweetening agents, etc., and any combination thereof. In some embodiments, the excipients may affect the properties of the coating in a number of ways, and thus many of the substances used in coating formulations may be described as multifunctional. Those skilled in the art will know, based on their technical knowledge, which excipients are suitable for the desired controlled-release coating composition.

[0211] The coating may contain hydrophilic agents to facilitate wetting of the coating upon contact with gastrointestinal fluids. Such hydrophilic agents include hydrophilic water-soluble polymers such as hydroxypropyl methylcellulose (HPMC) (e.g. 606 or hypromellose), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, polyvinylpyrrolidone ( or ), polyvinyl alcohol, polyethylene oxide, vinylpyrrolidone-vinyl acetate copolymer ( VA64), polyethylene glycol-polyvinyl alcohol copolymer ( IR), their copolymers, and combinations thereof. In at least one embodiment, HPMC is the hydrophilic agent used in the coating composition. In certain embodiments, the hydrophilic agent comprises a pH-dependent polymer, non-limiting examples of which include: cellulose acetate phthalate (e.g. CPD); cellulose acetate trimellitate, poly(methacrylic acid, ethyl acrylate) 1:1 (e.g. L30D-55); MAE 30D; poly(methacrylic acid, ethyl acrylate) 1:1 (e.g., Ll00-55); MAE30DP; FS 30D; hydroxypropyl methylcellulose acetate succinate LF, MF, HF grades (e.g., )), polyvinyl acetate phthalate, and mixtures thereof. If the coating composition contains a hydrophilic agent, then in certain embodiments, the agent may be present in an amount of from about 0.1% to about 10% by weight of the coating composition. In other embodiments, from about 0.1% to about 5% by weight of the coating composition, and in still other embodiments, from about 0.1% to about 3% by weight of the coating composition. In certain embodiments, the hydrophilic agent is present in an amount greater than about 0% to about 35% by dry weight of the coating. In other embodiments, the hydrophilic agent is present in an amount of from about 8% to about 30% by dry weight of the coating. In still other embodiments, the hydrophilic agent is present in an amount of from about 12% to about 26% by dry weight of the coating, e.g., about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, and about 25% by dry weight of the coating. In certain embodiments, the hydrophilic agent is present in an amount of from about 0% to about 14% by dry weight of the tablet; in other embodiments, in an amount of from about 0.2% to about 6% by dry weight of the tablet; and in still other embodiments, in an amount of from about 0.8% to about 2.5% by dry weight of the tablet; e.g., about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, and about 2.4% by dry weight of the tablet in the coating formulation.

[0212] The tackiness of the polymeric film is crucial for the coating of the dosage form and the subsequent curing step (post-coating heat treatment). During coating with cellulose or acrylic polymers, especially at higher product processing temperatures, undesirable and sometimes irreversible agglomeration of several particles or beads or, in the worst case, the entire batch may occur. Therefore, it is desirable to add an anti-tack agent to the coating formulation. Anti-tack agents that can be used include, but are not limited to, adipic acid, magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, sterotex, glycerol monostearate, talc (e.g., talc 400), sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and mixtures thereof. In at least one embodiment, talc (e.g., talc 400) is used as the anti-tack agent. Talc can also act as a wetting agent. Mixtures of anti-tack agents are feasible. The amount of the anti-tack agent in the coating composition of certain embodiments can range from about 1% to about 15% by weight of the coating dispersion, and in certain embodiments, is from about 1% to about 7% by weight of the coating dispersion. In certain embodiments, the anti-tack agent is present in an amount greater than about 0% to about 50% by weight of the dry coating. In other embodiments, the anti-tack agent is present in an amount from about 2% to about 40% by weight of the dry coating. In still other embodiments, the anti-tack agent is present in an amount from about 10% to about 30% by weight of the dry coating, such as about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, and about 29% by weight of the dry coating.In certain embodiments, the anti-sticking agent is present in an amount of from about 0% to about 20% by dry weight of the tablet; in other embodiments, in an amount of from about 0% to about 12% by dry weight of the tablet; and in still other embodiments, in an amount of from about 0.6% to about 7% by dry weight of the tablet; for example, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about 6%, about 6.1%, about 6.2%, about 6.3%, about 6.4%, about 6.5%, about 6.6%, about 6.7%, about 6.8% and about 6.9% by dry weight of the tablet is present in the coating formulation.

[0213] Antifoaming agents that may be included in the coating composition include silicone oils, dimethicone (e.g., dimethicone emulsion), and mixtures thereof. In some embodiments, the antifoaming agent is dimethicone. In certain embodiments, the antifoaming agent, if present, may be present in an amount up to about 0.5% by weight of the coating composition, and in certain other embodiments, in an amount of about 0.1% to about 0.4% by weight of the coating composition. In certain embodiments, the antifoaming agent is present in an amount greater than about 0% to about 3% by weight of the dry coating weight. In other embodiments, the antifoaming agent is present in an amount of about 0.4% to about 2% by weight of the dry coating weight. In still other embodiments, the antifoaming agent is present in an amount of about 0.8% to about 1.5% by weight of the dry coating weight, such as about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, and about 1.4% by weight of the dry coating weight. In certain embodiments, the antifoaming agent is present in an amount of about 0% to about 1.2% by weight of the tablet dry weight; in other embodiments, in an amount of about 0% to about 0.8% by weight of the tablet dry weight; and in still other embodiments, in an amount of about 0% to about 0.2% by weight of the tablet dry weight; for example, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, and about 0.19% by weight of the tablet dry weight in the coating formulation.

[0214] The incorporation of an emulsifying agent (also referred to as an emulsifier / emulgent) can be used to facilitate the actual emulsification during coating manufacture and can also be used to provide emulsion stability of the product during its shelf life. Emulsifying agents that can be used in the coating composition include, but are not limited to, naturally occurring materials and their semi-synthetic derivatives, such as polysaccharides, as well as glycerol esters, cellulose ethers, sorbitan esters, and polysorbates. Mixtures are viable. In at least one embodiment, the emulsifying agent used is polysorbate 80 (polyoxyethylene sorbitan monooleate), (e.g., (80). In certain embodiments, one or more emulsifiers (if present) may be present in an amount greater than 0% to about 0.5% by weight of the coating composition. In at least one embodiment, the emulsifier is present in an amount of about 0.1% to about 0.3% by weight of the coating composition. In certain embodiments, the emulsifier is present in an amount greater than about 0% to about 2% by weight of the dry coating weight. In other embodiments, the emulsifier is present in an amount of about 0.1% to about 1% by weight of the dry coating weight. In still other embodiments, the emulsifier is present in an amount of about 0.25% to about 0.75% (e.g., including about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65% and about 0.70%) by weight of the dry coating weight. In certain embodiments, the emulsifier is present in an amount greater than about 0% to about 0.8% by weight of the dry tablet weight; in other embodiments, in an amount greater than about 0% to about 0.4% by weight of the dry tablet weight; and in still other embodiments, in an amount greater than about 0% to about 0.2% by weight of the dry tablet weight; e.g., about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18% and about 0.19% by weight of the dry tablet weight in the coating formulation.

[0215] Any permitted colorant in the film coating formulation is a dye (pigment) that is always insoluble in water. Pigments have certain advantages compared to water-soluble dyes as they tend to have higher photochemical stability, provide better opacity and covering power, and optimize the water vapor impermeability of a given film. Examples of suitable colorants include, but are not limited to, iron oxide pigments, titanium dioxide, and aluminum lakes. Mixtures are feasible. In at least one embodiment, the pigment or colorant used is titanium dioxide. In certain embodiments, the pigment or colorant (if present) may be present in an amount of from about 0.1% to about 10% by weight of the coating composition. In at least one embodiment, the colorant is present in an amount of from about 0.1% to about 5% by weight of the coating composition. In at least one other embodiment, the colorant is present in an amount of from about 0.1% to about 2% by weight of the coating composition. In certain embodiments, the colorant is present in an amount of greater than about 0% to about 20% by weight of the dry coating weight. In other embodiments, the colorant is present in an amount of greater than about 0% to about 10% by weight of the dry coating weight. In still other embodiments, the colorant is present in an amount of from about 2.2% to about 6.2% (such as including about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about 6% and about 6.1%) by weight of the dry coating weight. In certain embodiments, the colorant is present in an amount of greater than about 0% to about 8% by weight of the dry tablet weight; in other embodiments, in an amount of greater than about 0% to about 5% by weight of the dry tablet weight; and in still other embodiments, in an amount of greater than about 0% to about 1% (such as including about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8% and about 0.9%) by weight of the dry tablet weight in the coating formulation.

[0216] In at least one embodiment, the second excipient in the controlled release coating comprises at least one of the following: a neutral ester copolymer without any functional groups (such as NE30D, NE40D, NM30D, EMM30D, or a mixture thereof), HPMC (such as 606), talcum powder (such as talcum powder 400), polyethylene glycol (such as polyethylene glycol 4000, polyethylene glycol 4600, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 12000, polyethylene glycol 20000, polyethylene glycol 35000, or a mixture thereof), dimethicone, polysorbate 80, titanium dioxide, and mixtures thereof.

[0217] In at least one embodiment, the stable controlled release coating undergoes a hydration reaction when placed in water. In at least one embodiment, the dosage form coated with the controlled release coating floats in water. In at least one embodiment, the controlled release dosage form will provide controlled release of an effective amount of the active drug to at least one region of the upper gastrointestinal tract (such as the stomach) of the patient after being orally administered to the patient.

[0218] In some embodiments, the controlled release coating is formed by a process that does not involve the use of organic solvents. In such embodiments, the controlled release coating composition is water-based rather than solvent-based (referred to as "AQ" in certain instances of dosage forms coated with a water-based controlled release coating). In some embodiments, the controlled release coating is formed by a solvent-based process (such as the "PharmaPASS" TM " composition).

[0219] The coating composition can be applied to the core containing an effective amount of the therapeutic active agent by a process involving atomizing (spraying) the coating composition (solution or suspension) onto the bed of the tablet core. Some examples of equipment suitable for film coating include: ACCELA (Manesty Machines, Liverpool, UK), (Freund Company, Japan), DRIACOATER TM (Driam Metallprodukt GmbH, Germany), HTF / 150 TM (GS, Italy) and IDA TM (Dumoulin, France). Examples of units operating on the fluidized bed principle include: AEROMATIC TM (Fielder, Switzerland and UK) and GLATT AG TM (Switzerland). In at least one embodiment, the equipment used is ACCELA

[0220] The coating composition is delivered from a peristaltic pump to a coating apparatus at the desired rate and sprayed onto the rotating or fluidized tablet cores. The tablet cores are preheated to about 30 °C. During the coating process, the product temperature range is maintained between about 25 °C and about 35 °C by adjusting the incoming and outgoing air flow rates, the incoming air temperature, and the spraying rate. A single layer of the coating composition is applied and once spraying is complete, the coated tablet cores are dried at a low pan speed and low air flow between about 30 °C and about 40 °C for about 3 to about 5 minutes. The pan is readjusted to a low speed and drying is continued for about 12 to about 15 minutes.

[0221] The coated tablet cores are placed on trays and cured (post - coating heat treatment) in an electric furnace or a steam furnace at a temperature above the melting point temperature of polyethylene glycol or its derivatives. In at least one embodiment, the curing temperature is above the melting point of polyethylene glycol or its derivatives. In at least one embodiment, the curing time is about 2 to about 7 hours. Subsequently, the cured coated tablets are cooled to about room temperature.

[0222] In some other embodiments, the coated tablet cores are placed on a coating pan and cured in two stages. During the first stage, the coated tablets are cured at a first curing temperature (e.g., between about 50 °C and about 59 °C in some embodiments) for a period of time (e.g., between about 15 minutes and about 90 minutes in some embodiments; and about 60 minutes in at least one embodiment). During the second stage, the coated tablets are cured at a second curing temperature that is at least equal to or greater than the melting point of polyethylene glycol (e.g., between about 60 °C and about 70 °C in some embodiments) for an additional period of time (e.g., between about 30 minutes and about 180 minutes in some embodiments; and for about 120 minutes in at least one embodiment). In at least one embodiment, the two - stage curing of the coated tablets reduces non - functional defects on the tablets caused by the curing process. In at least one embodiment, the two - stage curing process substantially eliminates non - functional defects on the tablets caused by the curing process. Non - functional defects on the dosage form caused by the curing process may include: visual defects of the coating (e.g., poor color uniformity and / or dull appearance), defects on the coating surface (e.g., roughness of the coating surface and / or wrinkles in the coating), and sticking of the tablets to each other and / or to the coating pan. In addition, the reduction of defects in terms of tablet color and smoothness improves the printing of the tablets.

[0223] In some embodiments, coating formulations are used to coat a variety of calcium α-ketoglutarate cores and can be adjusted to obtain a desired drug release profile. The length and timing of the delay are controlled by the hydration rate and the coating thickness. The drug release rate after the delay is determined by the thickness and permeability of the hydrated coating. Thus, the hydration rate and permeability of the coating can be regulated so that a desired controlled release drug profile can be obtained. There is no preferred coating thickness as this will depend on the drug used in the core and the desired controlled release profile.

[0224] Other parameters in combination with the coating thickness include varying the concentration of some of the components of the stabilizing coating composition and / or varying the curing temperature and duration for curing the coated tablet cores. Those skilled in the art will know which parameters or combinations of parameters to vary for a desired controlled release profile.

[0225] Immediate release coating formulation

[0226] In some embodiments, the immediate release coating contains calcium α-ketoglutarate and the additives described herein. In some embodiments, an effective amount of an immediate release active agent is coated onto the formulations described herein in immediate release form. For example, if the extended release of calcium α-ketoglutarate from the formulation is due to a controlled release coating, then an immediate release layer of the additive will be overlaid on top of the controlled release coating. In some embodiments, an immediate release layer of the additive is coated onto the surface of a substrate in which the controlled release matrix is admixed with calcium α-ketoglutarate. When incorporating a variety of sustained release substrates (e.g., multi-particle systems including pellets, spherules, beads, etc.) containing an effective unit dose of calcium α-ketoglutarate into a hard gelatin capsule, a compound that reduces side effects can be incorporated into the gelatin capsule by including a sufficient amount of an immediate release antihistamine or antiemetic in powder or granule form within the gelatin capsule. Alternatively, the gelatin capsule itself may be coated with an immediate release layer of the additive.

[0227] A coating containing an immediate release additive (such as an antihistamine or antiemetic) can be added to the outside of the controlled release tablet core to produce the final dosage form. Such a coating can be prepared by mixing a compound such as promethazine with polyvinylpyrrolidone (PVP) 29 / 32 or hydroxypropylmethylcellulose (HPMC) and water / isopropyl alcohol and triethyl acetate. Such an immediate release coating can be sprayed onto the tablet core. The immediate release coating can also be applied using a press coating process with a blend consisting of 80% by weight promethazine, 20% by weight lactose, and hydroxypropylmethylcellulose type 2910.

[0228] In some embodiments, the immediate release / controlled release dosage forms described herein form a bilayer tablet comprising a first layer and a second layer. In some embodiments of the bilayer tablet, the first layer is the immediate release layer and / or the second layer is the controlled release layer.

[0229] Formulations and Routes of Administration

[0230] The sustained release compositions of calcium α-ketoglutarate disclosed herein can be formulated in a conventional manner using one or more physiologically acceptable carriers, which carriers include excipients and auxiliaries that aid in processing the active compound into a pharmaceutically acceptable article. Suitable formulations depend on the chosen route of administration. Additional details regarding suitable excipients for the compositions described herein can be found, for example, in the following: Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., editors, Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), such disclosures being incorporated herein by reference.

[0231] The compositions of calcium α-ketoglutarate described herein are administered to a subject by a variety of routes of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, inhalation, buccal, topical, rectal, or transdermal routes of administration. In some embodiments, the compositions comprising calcium α-ketoglutarate described herein are formulated into any suitable dosage form, including but not limited to emulsions suitable for injection, nano-suspensions suitable for injection, oral aqueous dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, fast-dissolving formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multi-particulate formulations, and immediate release / controlled release hybrid formulations.

[0232] In some embodiments, calcium α-ketoglutarate is calcium α-ketoglutarate monohydrate. In some embodiments, the composition is an oral preparation, a buccal preparation, a nasal preparation, or an inhalation preparation. In some embodiments, the composition is in the form of a tablet or a capsule.

[0233] In some embodiments, the composition for oral use is a tablet (including a suspension tablet, an instant tablet, a bite-disintegration tablet, a fast-disintegration tablet, an effervescent tablet, or a sachet tablet), a pellet, a powder (including a sterile-packaged powder, a dispensable powder, or an effervescent powder), a capsule (including a soft capsule or a hard capsule, such as a capsule made of animal-derived gelatin or plant-derived HPMC, or a "sprinkle capsule"), a solid dispersion, a solid solution, a bioerodible dosage form, a controlled-release preparation, a pulsatile-release preparation, a multi-particle dosage form, a pellet, a granule, or an aerosol. In some embodiments, the composition for oral use is a solid dosage form, such as a tablet, an effervescent tablet, and a capsule. In some embodiments, the solid dosage form is prepared by mixing particles of calcium α-ketoglutarate with one or more pharmaceutically acceptable excipients to form a bulk blend composition. When referring to these bulk blend compositions as homogeneous, it means that the particles of calcium α-ketoglutarate are uniformly dispersed throughout the composition such that the composition can be re-divided into equally effective unit dosage forms, such as tablets, pills, and capsules. The individual unit doses may also include a film coating that disintegrates after oral ingestion or after contact with a diluent.

[0234] For oral administration, the compositions disclosed herein can be readily formulated by combining one or more active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compositions disclosed herein to be formulated into tablets (including chewable tablets), pills, dragees, capsules, lozenges, hard candies, liquids, gels, syrups, slurries, powders, suspensions, elixirs, wafers, etc. for oral ingestion by the patient to be treated. Such preparations may contain pharmaceutically acceptable carriers, including solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Generally, the compositions disclosed herein will be included at a concentration level of about 0.5%, about 5%, about 10%, about 20%, or about 30% to about 50%, about 60%, about 70%, about 80%, or about 90% by weight of the total composition of the oral dosage form in an amount sufficient to provide the desired dosage unit.

[0235] Additives

[0236] In some embodiments, the sustained release composition of calcium α-ketoglutarate further comprises one or more agents. In some embodiments, the one or more agents are selected from the group consisting of surfactants, preservatives, flavoring agents, vitamins, antioxidants, and sweeteners.

[0237] In some embodiments, the composition comprises vitamins. In some embodiments, the vitamins are vitamin A, vitamin B, vitamin C, or vitamin D.

[0238] In some embodiments, the vitamin is vitamin A. In some embodiments, the amount of vitamin A is from 500 IU to 5000 IU. In some embodiments, the amount of vitamin A is from 1000 IU to 3000 IU. In some embodiments, the amount of vitamin A is from 1000 IU to 2000 IU. In some embodiments, the amount of vitamin A is at least 500 IU. In some embodiments, the amount of vitamin A is at most 5,000 IU.In some embodiments, the amount of vitamin A is from 500 IU to 750 IU, from 500 IU to 1,000 IU, from 500 IU to 1,500 IU, from 500 IU to 2,000 IU, from 500 IU to 2,500 IU, from 500 IU to 3,000 IU, from 500 IU to 3,500 IU, from 500 IU to 4,000 IU, from 500 IU to 4,500 IU, from 500 IU to 5,000 IU, from 750 IU to 1,000 IU, from 750 IU to 1,500 IU, from 750 IU to 2,000 IU, from 750 IU to 2,500 IU, from 750 IU to 3,000 IU, from 750 IU to 3,500 IU, from 750 IU to 4,000 IU, from 750 IU to 4,500 IU, from 750 IU to 5,000 IU, from 1,000 IU to 1,500 IU, from 1,000 IU to 2,000 IU, from 1,000 IU to 2,500 IU, from 1,000 IU to 3,000 IU, from 1,000 IU to 3,500 IU, from 1,000 IU to 4,000 IU, from 1,000 IU to 4,500 IU, from 1,000 IU to 5,000 IU, from 1,500 IU to 2,000 IU, from 1,500 IU to 2,500 IU, from 1,500 IU to 3,000 IU, from 1,500 IU to 3,500 IU, from 1,500 IU to 4,000 IU, from 1,500 IU to 4,500 IU, from 1,500 IU to 5,000 IU, from 2,000 IU to 2,500 IU, from 2,000 IU to 3,000 IU, from 2,000 IU to 3,500 IU, from 2,000 IU to 4,000 IU, from 2,000 IU to 4,500 IU, from 2,000 IU to 5,000 IU, from 2,500 IU to 3,000 IU, from 2,500 IU to 3,500 IU, from 2,500 IU to 4,000 IU, from 2,500 IU to 4,500 IU, from 2,500 IU to 5,000 IU, from 3,000 IU to 3,500 IU, from 3,000 IU to 4,000 IU, from 3,000 IU to 4,500 IU, from 3,000 IU to 5,000 IU, from 3,500 IU to 4,000 IU, from 3,500 IU to 4,500 IU, from 3,500 IU to 5,000 IU, from 4,000 IU to 4,500 IU, from 4,000 IU to 5,000 IU, or from 4,500 IU to 5,000 IU. In some embodiments, the amount of vitamin A is about 500 IU. In some embodiments, the amount of vitamin A is about 750 IU. In some embodiments, the amount of vitamin A is about 1,000 IU. In some embodiments, the amount of vitamin A is about 1,500 IU. In some embodiments, the amount of vitamin A is about 2,000 IU.In some embodiments, the amount of vitamin A is about 2,500 IU. In some embodiments, the amount of vitamin A is about 3,000 IU. In some embodiments, the amount of vitamin A is about 3,500 IU. In some embodiments, the amount of vitamin A is about 4,000 IU. In some embodiments, the amount of vitamin A is about 4,500 IU. In some embodiments, the amount of vitamin A is about 5,000 IU.

[0239] In some embodiments, the vitamin is vitamin D. In some embodiments, the amount of vitamin D is from 100 IU to 3000 IU. In some embodiments, the amount of vitamin D is from 200 IU to 2000 IU. In some embodiments, the amount of vitamin D is from 250 IU to 1000 IU. In some embodiments, the amount of vitamin D is from 100 IU to 3000 IU. In some embodiments, the amount of vitamin D is at least 100 IU. In some embodiments, the amount of vitamin D is at most 3,000 IU. In some embodiments, the amount of vitamin D is 100 IU to 250 IU, 100 IU to 500 IU, 100 IU to 750 IU, 100 IU to 1,000 IU, 100 IU to 1,250 IU, 100 IU to 1,500 IU, 100 IU to 1,750 IU, 100 IU to 2,000 IU, 100 IU to 2,500 IU, 100 IU to 3,000 IU, 250 IU to 500 IU, 250 IU to 750 IU, 250 IU to 1,000 IU, 250 IU to 1,250 IU, 250 IU to 1,500 IU, 250 IU to 1,750 IU, 250 IU to 2,000 IU, 250 IU to 2,500 IU, 250 IU to 3,000 IU, 500 IU to 750 IU, 500 IU to 1,000 IU, 500 IU to 1,250 IU, 500 IU to 1,500 IU, 500 IU to 1,750 IU, 500 IU to 2,000 IU, 500 IU to 2,500 IU, 500 IU to 3,000 IU, 750 IU to 1,000 IU, 750 IU to 1,250 IU, 750 IU to 1,500 IU, 750 IU to 1,750 IU, 750 IU to 2,000 IU, 750 IU to 2,500 IU, 750 IU to 3,000 IU, 1,000 IU to 1,250 IU, 1,000 IU to 1,500 IU, 1,000 IU to 1,750 IU, 1,000 IU to 2,000 IU, 1,000 IU to 2,500 IU, 1,000 IU to 3,000 IU, 1,250 IU to 1,500 IU, 1,250 IU to 1,750 IU, 1,250 IU to 2,000 IU, 1,250 IU to 2,500 IU, 1,250 IU to 3,000 IU, 1,500 IU to 1,750 IU, 1,500 IU to 2,000 IU, 1,500 IU to 2,500 IU, 1,500 IU to 3,000 IU, 1,750 IU to 2,000 IU, 1,750 IU to 2,500 IU, 1,750 IU to 3,000 IU, 2,000 IU to 2,500 IU, 2,000 IU to 3,000 IU or 2,500 IU to 3,000 IU.In some embodiments, the amount of vitamin D is about 100 IU. In some embodiments, the amount of vitamin D is about 250 IU. In some embodiments, the amount of vitamin D is about 500 IU. In some embodiments, the amount of vitamin D is about 750 IU. In some embodiments, the amount of vitamin D is about 1,000 IU. In some embodiments, the amount of vitamin D is about 1,250 IU. In some embodiments, the amount of vitamin D is about 1,500 IU. In some embodiments, the amount of vitamin D is about 1,750 IU. In some embodiments, the amount of vitamin D is about 2,000 IU. In some embodiments, the amount of vitamin D is about 2,500 IU. In some embodiments, the amount of vitamin D is about 3,000 IU.

[0240] In some embodiments, the vitamin is nicotinamide riboside (NR). In some embodiments, the vitamin is nicotinamide mononucleotide (NMN).

[0241] In some embodiments, the composition may comprise an antioxidant. In some embodiments, the antioxidant is fisetin.

[0242] Examples

[0243] The following examples are for illustrative purposes only and are intended solely as examples of the present disclosure and are not intended to limit the scope of the claims provided herein.

[0244] Example 1. General manufacturing procedure for calcium α-ketoglutarate sustained-release tablets. Exemplary tablets include 350-450 mg of α-ketoglutaric acid by weight based on the free acid. Further, exemplary tablets include 450-650 mg of α-ketoglutaric acid compounds by weight based on the salt form and the hydrate form. Further, when the α-ketoglutaric acid compound is a calcium salt, the exemplary tablets include 150-250 mg of calcium by weight. The average weight of the uncoated tablets is about 1000-1000 mg, including about 1030 mg. The average weight of the coated tablets is about 1020-1120 mg, including about 1060 mg. Exemplary tablet cores include the following:

[0245] Tablet Core 1

[0246]

[0247] Tablet Core 2

[0248]

[0249]

[0250] Exemplary coatings include the following:

[0251] Coating

[0252]

[0253] Calculation

[0254] For example, calcium α-ketoglutarate monohydrate corresponds to:

[0255] α-ketoglutaric acid = 350 mg;

[0256] Conversion factor = 1.26 (for anhydrous α-ketoglutaric acid compounds);

[0257] Converted amount = 441 mg;

[0258] Standard LOD = 10%; Standard assay content = 98%;

[0259] Standard calculation: (441 x 100 x 100) / (98 × (100 - 10)) = 500 mg;

[0260] Also contains elemental calcium = 19.5 to 22%;

[0261] Considering the lowest value = 19.5%;

[0262] 500 mg CAKG contains 97.5 mg of elemental calcium.

[0263] Standard manufacturing process

[0264] 1. Weighing

[0265] Weigh all ingredients according to the quantities given in the manufacturing formula.

[0266] 2. Sieving

[0267] Mix 290.0 gm of HPMC K4 and 435.0 gm of HPMC Kl5 in a double-cone blender for 5 minutes and sieve through a 40# sieve. Sieve 686.0 gm of lactose monohydrate and 954.0 gm of microcrystalline cellulose through a 40# sieve. Then mix with 2500.0 gm of calcium α-ketoglutarate monohydrate for 2 minutes and sieve through a 30# sieve. Sieve 50.0 gm of colloidal silicon dioxide through a 40# sieve and 50.0 gm of magnesium stearate through a 60# sieve. Collect each sieved material separately in plastic bags. (Temperature and RH should be NMT 27°C and 40% RH throughout the process)

[0268] 3. Mixing & Granulation

[0269] Mix the above-screened ingredients (HPMC K4 and HPMC Kl 5, calcium α-ketoglutarate monohydrate, lactose monohydrate, colloidal silicon dioxide, and microcrystalline cellulose) in a double-cone blender (capacity 18 liters) at 16 rpm for 25 minutes. Add magnesium stearate to the above blend and mix in a double-cone blender (capacity 18 liters) for 5 minutes.

[0270] 4. Slugging

[0271] Use a suitable punch size and tablet press to compress the dry blend material obtained in the previous step to obtain tablets. Punch description: 19 6x8.4 mm, capsule-shaped, standard concave, flat punch. Hardness: 2 - 5 kg / cm 2 。

[0272] 5. Dressing

[0273] Grind the tablets using a 6.0 mm S.S. sieve and perform final sizing of the granules via an 18# sieve. Note: (Perform slugging and dressing twice to obtain granules with suitable flow characteristics).

[0274] Parameters of the dressed granules (target):

[0275] 1) Bulk density - 0.6 to 0.7 gm / ml;

[0276] 2) Tapped density - 0.9 to 1.0 gm / ml;

[0277] 3) Carr's index - 25 - 30%; and

[0278] 4) Hausner ratio - 1.3 to 1.4.

[0279] 6. Lubrication

[0280] Check the integrity of the sieve before use. Screen 98.75 gm of colloidal silicon dioxide via a 40# sieve. Screen 86.25 gm of magnesium stearate via a 60# sieve. Mix the dressed material from step 5 with colloidal silicon dioxide in a double-cone blender for 5 minutes. Add magnesium stearate to the above blend in a double-cone blender and hold for 5 minutes. Collect the lubricated granules in a double-layer polyethylene bag and keep tightly closed. In some embodiments, one or more of a flavoring agent, a vitamin, an antioxidant, and a sweetening agent are added to the composition together with magnesium stearate and / or colloidal silicon dioxide during the lubrication step.

[0281] 7. Compress tablets

[0282] Environmental parameters:

[0283] 1) RH - NMT 40%;

[0284] 2) Temperature - NMT 27 °C;

[0285] Air pressure difference - NLT 10 Pascals;

[0286] * Punch type: "D" die;

[0287] 19.6 x 8.4 mm, capsule - shaped, standard concave. Flat punch.

[0288] Check the complete rotation of the turret by turning the handwheel and then electrically. Feed the granules and set the machine according to the required specifications. Check the tablets produced by one complete rotation.

[0289] 8. Film coating of tablets

[0290] Disperse Instamoistshield white (ICMS 2398) into a given amount of isopropyl alcohol under stirring. Stir for a further 5 minutes. Add dichloromethane to the above - mentioned given amount under continuous stirring, and stir for a further 40 - 45 minutes to obtain a white, viscous, lump - free suspension. Pass the above suspension through a colloid mill via an "O" - type adjustment gap for 15 minutes. Filter the coating suspension through a 200 - mesh nylon cloth. Turn on the exhaust device, and apply the film - coating suspension to the tablets using a clean spray gun assembly (ensuring aesthetics), and continue to stir the coating suspension during tablet coating. After appropriate weight build - up (300%), dry the film - coated tablets sufficiently. The target average weight of the film - coated tablets = 1060.0 mg. Once the target weight gain is achieved, dry the film - coated tablets in the coating pan for 30 minutes.

[0291] Example 2. Dissolution profile of calcium α - ketoglutarate sustained release

[0292] [Dissolution parameters]

[0293] Medium: 900 mL of enzyme - free simulated gastric fluid (SGF)

[0294] Equipment: Paddle type (with sinker)

[0295] Speed: 75 rpm

[0296] Time: 1st hour, 4th hour, 8th hour, and 12th hour.

[0297] [Chromatography conditions]

[0298] Column: Inertsil ODS, 3V (250 x 4.6 mm) 5um or equivalent;

[0299] Flow rate: 0.8 mL / min

[0300] Wavelength: 210 nm

[0301] Injection volume: 10 uL

[0302] Oven temperature: 30 °C

[0303] Sample cooler temperature: 15 °C

[0304] Elution mode: Isocratic

[0305] Enzyme-free simulated gastric fluid (SGF) (dissolution medium): Weigh 2.0 gm of sodium chloride and 7.0 mL of concentrated hydrochloric acid and transfer to 1000 mL of water and mix.

[0306] Buffer solution: Dissolve 2.72 gm of potassium dihydrogen phosphate in 1000 mL of water and add 2.0 mL of phosphoric acid.

[0307] Mobile phase: Prepare a mixture of 95 volumes of buffer and 5 volumes of acetonitrile, mix, filter, and degas before use.

[0308] Standard solution: Weigh accurately 55 mg of calcium α-ketoglutarate working standard and transfer to a 100 mL dry volumetric flask, add 50 mL of dissolution medium. Dissolve with dissolution medium and make up the volume and mix.

[0309] Test solution: Set the dissolution parameters, place one tablet in each container, carefully remove the air bubbles on the tablet surface, and immediately start the equipment. After 1 hour, 4 hours, 8 hours, and 12 hours, withdraw 10 mL of the medium sample and replace the withdrawn volume with fresh fluid. Filter the sample withdrawn through a 0.45 micron nylon syringe filter; discard the first few milliliters of the filtrate.

[0310] System suitability: Inject the standard solution five times repeatedly. The relative standard deviation of the repeated injections does not exceed 2%.

[0311] Procedure: Inject 10 uL of each test solution into the liquid chromatograph and record the chromatogram. Measure the response of the calcium α-ketoglutarate peak. Calculate the drug release percentage of calcium α-ketoglutarate from the peak area of calcium α-ketoglutarate of the standard and test the potency percentage of the working standard used.

[0312] Injection order:

[0313]

[0314]

[0315] Calculation:

[0316] (AT / AS) x (W / 100) x (900 / LC) x (p / 100) x 100

[0317] Wherein,

[0318] AT - The peak area of calcium α-ketoglutarate in the chromatogram obtained from each injection of the test solution;

[0319] AS - The average peak area of calcium α-ketoglutarate in the chromatograms obtained from five repeated injections of the standard solution;

[0320] WS - The weight of the calcium α-ketoglutarate working standard, in mg; LC - The labeled value;

[0321] P - The potency of the calcium α-ketoglutarate working standard based on this.

[0322] Correction factor:

[0323] (Volume withdrawn × % dissolution (labeled value %) / Volume of dissolution medium at the above time intervals for the 1-hour time point = % dissolution after 1 hour;

[0324] For the 4-hour time point = Correction factor for the 1-hour time point + % dissolution after 4 hours;

[0325] For the 8-hour time point = Correction factor for the 1-hour time point + Correction factor for the 4-hour time point + % dissolution after 8 hours;

[0326] For the 12-hour time point = Correction factor for the 1-hour time point + % Correction factor for the 4-hour time point +

[0327] Correction factor for the 8-hour time point + % dissolution after 12 hours;

[0328] Results:

[0329] Batch A (Dissolution, %)

[0330]

[0331] Batch B (Dissolution, %)

[0332]

[0333] Although the preferred embodiments of the present disclosure have been shown and described herein, such embodiments are provided by way of example only, which will be apparent to those skilled in the art. Various variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be used to practice the invention. It is intended that the appended claims define the scope of the present disclosure and that methods and structures within the scope of these claims and their equivalents are thereby covered.

[0334] Method Example 1. Extend the healthy period and / or lifespan of mice. Feed 18-month-old non-genetically modified mice a control diet, optionally a control diet plus an immediate-release formulation (positive control), or a control diet plus the composition described herein (treatment group). Instead of sacrificing the mice, let them die naturally. Compare the lifespans of the mice in the treatment group, the control group, and optionally the positive control group. In addition to lifespan determination, the frailty of the mice is measured throughout the study by a non-invasive frailty index composed of 31 observations, adapted from a clinically relevant frailty index. Compared to the control group and the positive control group of both genders, the composition described herein extends lifespan, healthy period, and / or improves frailty. Other details of the example are described in Lucanic, M., Lithgow, G. J., & Alavez, S. (2013). Pharmacological lifespan extension of invertebrates. Ageing research reviews, 12(1), 445-458; Searle, S. D., Mitnitski, A., Gahbauer, E. A., Gill, T. M., & Rockwood, K. (2008). A standard procedure for creating a frailty index. BMC geriatrics, 8(1), 24; and Whitehead (2014.).

[0335] Method Example 2. Extend the healthy period and / or lifespan of humans (male and female). Administer the composition described herein orally or parenterally to male and female volunteers and compare with a control group receiving a placebo, and optionally with a positive control group receiving a commercially available Ca-AKG (such as immediate-release Ca-AKG). One or more of the conventional frailty index observations among the 31 frailty index observations are used to monitor the lifespan, healthy period, and frailty of the volunteers. This study is an open-label study comparing the treatment group, the control group, and optionally the positive control group. Evaluate the volunteers at the following three time points: at the start of the study (day 1), 3 months, and 6 months. Obtain blood pressure, heart rate, weight, safety labs, CRP, blood chemistry, hemoglobin A1C, and uric acid levels at each visit, and have each participant complete a study questionnaire.

[0336] Blood chemistry was used to calculate the biological age of the participants via one or more published algorithms, such as the methods described in the following reference: Belsky, D. W., Caspi, A., Houts, R., Cohen, H. J., Corcoran, D. L., Danese, A., & Sugden, K. (2015). Quantification of biological aging in young adults. Proceedings of the National Academy of Sciences, 112(30), E4104 - E4110.

[0337] In an exemplary study design, volunteers were divided into a control group, an optional positive control group, or a treatment group, and each volunteer took two tablets daily for six months. The control group took a placebo, the positive control group took an immediate - release formulation, and the treatment group took the following two tablets:

[0338] For men: a tablet containing 500 mg calcium α - ketoglutarate monohydrate, 450 mcg retinyl palmitate, and one or more release modifiers;

[0339] For women: a tablet containing 500 mg calcium α - ketoglutarate monohydrate, 12.5 mcg (500 IU) cholecalciferol, and one or more release modifiers.

[0340] One or more primary outcomes were evaluated for each group. The primary outcomes were determined by measuring the following vital signs and blood chemistry:

[0341] Vital signs

[0342] Height

[0343] Weight

[0344] Blood pressure

[0345] Heart rate

[0346] Complete blood count

[0347] WBC (white blood cell count)

[0348] Hemoglobin

[0349] Hematocrit

[0350] Platelet count / L

[0351] MCV (mean corpuscular volume)

[0352] MCH (mean corpuscular hemoglobin)

[0353] MCHC (Mean Corpuscular Hemoglobin Concentration)

[0354] RBC (Red Blood Cell Count)

[0355] RDW-CV (Red Blood Cell Distribution Width)

[0356] MPV (Mean Platelet Volume)

[0357] Neutrophil

[0358] Neutrophil %

[0359] Lymphocyte Count

[0360] Lymphocyte %

[0361] Monocyte Count

[0362] Monocyte %

[0363] Eosinophil

[0364] Eosinophil %

[0365] Basophil

[0366] Basophil %

[0367] Comprehensive Metabolic Panel

[0368] Sodium

[0369] Potassium

[0370] Chloride Ion

[0371] Carbon Dioxide (CO2)

[0372] Blood Urea Nitrogen (BUN)

[0373] Creatinine

[0374] Glucose

[0375] Calcium

[0376] AST (Aspartate Aminotransferase)

[0377] ALT (Alanine Aminotransferase)

[0378] ALP (Alkaline Phosphatase)

[0379] Total Bilirubin

[0380] Alkaline Phosphatase

[0381] Albumin

[0382] Total Protein

[0383] Anion gap

[0384] MDRD-estimated glomerular filtration rate (eGFR)

[0385] Lipidome

[0386] Total cholesterol

[0387] LDL (low-density lipoprotein) cholesterol

[0388] HDL (high-density lipoprotein) cholesterol

[0389] Triglycerides

[0390] Additional laboratory tests

[0391] Hemoglobin A1C

[0392] Uric acid

[0393] Incorporated by reference

[0394] All publications, patents, and patent applications disclosed herein are hereby incorporated by reference as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein to the extent set forth.

Claims

1. A composition comprising (a) a therapeutically effective amount of calcium α-ketoglutarate, and (b) a controlled release matrix, said controlled release matrix comprising a first hydroxypropyl methylcellulose HPMC having a number average molecular weight in the range of 68,000 to 95,000 and a second hydroxypropyl methylcellulose HPMC having a number average molecular weight in the range of 115,000 to 150,000.

2. The composition according to claim 1, wherein the amount of calcium α-ketoglutarate is 30% to 65% by total weight of the composition.

3. The composition according to claim 1 or 2, which comprises 250 to 1000 mg of calcium α-ketoglutarate.

4. The composition according to claim 1 or 2, which comprises 350 to 1000 mg of calcium α-ketoglutarate.

5. The composition according to claim 1 or 2, which comprises 400 to 600 mg of calcium α-ketoglutarate.

6. The composition according to claim 1 or 2, which comprises about 525 mg of calcium α-ketoglutarate.

7. The composition according to claim 1 or 2, which comprises at least about 10% dietary value of calcium.

8. The composition according to claim 1 or 2, which comprises at least about 15% dietary value of calcium.

9. The composition according to any one of claims 1-2, which further comprises one or more excipients.

10. The composition according to any one of claims 1-2, which further comprises microcrystalline cellulose.

11. The composition according to any one of claims 1-2, which further comprises lactose monohydrate.

12. The composition according to any one of claims 1-2, which further comprises one or more lubricants.

13. The composition according to claim 12, wherein the lubricant is magnesium stearate.

14. The composition according to any one of claims 1-2, which further comprises one or more disintegrants.

15. The composition according to claim 14, wherein the disintegrant is silicon dioxide.

16. The composition according to any one of claims 1-2, which further comprises a sweetening agent.

17. The composition according to claim 16, wherein the sweetening agent is isomaltulose.

18. The composition according to any one of claims 1-2, which further comprises wax.

19. The composition according to claim 18, wherein the wax is carnauba wax and / or rice bran wax.

20. The composition according to any one of claims 1-2, characterized in that The release rate of the calcium α-ketoglutarate is uncontrolled or about 90% or less of the calcium α-ketoglutarate release rate of a calcium α-ketoglutarate composition formulated in the absence of the controlled release matrix.

21. The composition according to any one of claims 1-2, characterized in that The release rate of the calcium α-ketoglutarate is uncontrolled or about 70% or less of the calcium α-ketoglutarate release rate of a calcium α-ketoglutarate composition formulated in the absence of the controlled release matrix.

22. The composition according to any one of claims 1-2, characterized in that The release rate of the calcium α-ketoglutarate is uncontrolled or about 60% or less of the calcium α-ketoglutarate release rate of a calcium α-ketoglutarate composition formulated in the absence of the controlled release matrix.

23. The composition according to any one of claims 1-2, characterized in that The release rate of said calcium α-ketoglutarate is uncontrolled or about 50% or less of the calcium α-ketoglutarate release rate of a calcium α-ketoglutarate composition formulated in the absence of said controlled release matrix.

24. The composition according to any one of claims 1-2, characterized in that Measured by a paddle apparatus with a basket rotating at 75 rpm, after a time between 0.5 and 2 hours in the dissolution medium, the release rate of said calcium α-ketoglutarate is about 30% or less, wherein the dissolution medium is 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37 °C.

25. The composition according to any one of claims 1-2, characterized in that Measured by a paddle apparatus with a basket rotating at 75 rpm, after a time between 10 and 11 hours in the dissolution medium, the release rate of said calcium α-ketoglutarate is about 75% or more, wherein the dissolution medium is 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37 °C.

26. The composition according to any one of claims 1-2, wherein the calcium α-ketoglutarate is calcium α-ketoglutarate monohydrate.

27. The composition according to any one of claims 1-2, which is in the form of a dosage unit.

28. The composition according to any one of claims 1-2, which is in the form of a dosage unit configured for oral administration.

29. The composition according to any one of claims 1-2, which is in tablet form.

30. The composition according to any one of claims 1-2, which is in capsule form.

31. A tablet comprising 525 mg of calcium α-ketoglutarate monohydrate, a first hydroxypropyl methylcellulose HPMC having a number average molecular weight in the range of 68,000 to 95,000, and a second hydroxypropyl methylcellulose HPMC having a number average molecular weight in the range of 115,000 to 150,000.

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