Sustained-release compositions of alpha-ketoglutarate

Abstract

To provide sustained-release compositions of alpha-ketoglutarate.SOLUTION: A composition comprising (a) a therapeutically effective amount of calcium alpha-ketoglutarate, and (b) a controlled-release matrix.SELECTED DRAWING: None

Description

[Technical Field]

[0001] [Background technology]

[0002] Alpha-ketoglutarate is an important biomolecule, a key intermediate in the Krebs cycle, a nitrogen transporter, and a co-substrate for molecular oxidation. Alpha-ketoglutarate anions play a key role in metabolism, primarily in aerobic organisms. The calcium salt of alpha-ketoglutarate (Ca-AKG) is an important source of alpha-ketoglutarate anions. Currently available Ca-AKG is formulated for immediate release. Such known delivery methods release Ca-AKG within a short period of time, resulting in spikes in blood levels, faster excretion, and increased frequency of Ca-AKG administration. Therefore, there is a need to discover alternative methods for delivering Ca-AKG. Summary of the Invention [Problem to be solved by the invention]

[0003] It has been unexpectedly discovered that when alpha-ketoglutarate is released initially in the stomach or upper gastrointestinal (GI) tract, the overall bioavailability of alpha-ketoglutarate is variable and / or reduced, resulting in less predictable dosing guidance and less predictable clinical outcomes. Controlled-release, sustained-release, and / or delayed-release formulations of Ca-AKG have been discovered. Described herein are formulations of alpha-ketoglutarate with modified release characteristics, including controlled-release, sustained-release, and / or delayed-release characteristics. In one exemplary embodiment of the present invention, (a) a therapeutically effective amount of calcium alpha-ketoglutarate; (b) a controlled release matrix; The present invention describes a composition comprising: (a) a calcium alpha-ketoglutarate composition comprising: (a) a calcium alpha-ketoglutarate composition comprising: (a) a calcium alpha-ketoglutarate composition comprising: (a) a calcium alpha-ketoglutarate composition comprising: (a) a calcium alpha-ketoglutarate composition comprising: (b ...b) a calcium alpha-ketoglutarate composition comprising: (c) a calcium alpha-ketoglutarate composition comprising: (c) a calcium alpha-ketoglutarate composition comprising: (c) a calcium alpha-ketoglutarate composition comprising: (a) a calcium alpha-ketoglutarate composition comprising: (a) a calcium alpha-ketoglutarate composition comprising: (b) a calcium alpha-ketoglutarate composition comprising: (c) a calcium alpha-ketoglutarate composition comprising: (c) a calcium alpha-ketoglutarate composition comprising: (a) a calcium alpha-ketoglutarate composition comprising: (a) a calcium alpha-ketoglutarate composition comprising: (b) a calcium alpha-ketoglutarate composition comprising: (c) a calcium alpha-ketoglutarate composition comprising: (c) a calcium alpha-keto

[0004] In another embodiment, described herein is a composition comprising calcium alpha-ketoglutarate and one or more agents selected from the group consisting of surfactants, preservatives, flavoring agents, vitamins, antioxidants, sweeteners, and combinations thereof.

[0005] In another embodiment, also disclosed herein is a method for treating a psoriasis-associated rhombohedron comprising: with 525mg of calcium alpha-ketoglutarate; one or more release-modifying agents, Including, Optionally, the composition further comprises one or more of isomalt, vegetable wax (carnauba and / or rice bran), stearic acid, magnesium stearate, and silica.

[0006] In another embodiment, also disclosed herein is a method for treating a psoriasis-associated rhombohedron comprising: with 500-550 mg of calcium alpha-ketoglutarate; with 450mcg of retinyl palmitate; one or more release-modifying agents, Including, Optionally, the composition further comprises one or more of isomalt, vegetable wax (carnauba and / or rice bran), stearic acid, magnesium stearate, and silica.

[0007] In another embodiment, also disclosed herein is a method for treating a psoriasis-associated rhombohedron comprising: with 500-550 mg of calcium alpha-ketoglutarate; Cholecalciferol 12.5mcg (500IU) and; one or more release-modifying agents, Including, Optionally, the composition further comprises one or more of isomalt, vegetable wax (carnauba and / or rice bran), stearic acid, magnesium stearate, and silica.

[0008] It should be understood that in the formulations described herein, such release-modifying agents may 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 and one or more additional components of the composition, such as a combination of Ca-AKG and one or more vitamins.

[0009] Surprisingly, it has been found that the formulations described herein can contain low doses of active ingredients, including low doses of AKG and / or its salt, compared with alternative formulations that are formulated without any controlled release matrix or that otherwise release active ingredients in an uncontrolled manner.Without being bound by theory, it is believed herein that the formulations described herein result in higher overall bioavailability, and therefore can be administered in lower doses to achieve similar results. DETAILED DESCRIPTION OF THE INVENTION

[0010] Exemplary embodiments of the present invention are described in the following sections: A composition comprising a unit dose or dosage form, the composition comprising: (a) a therapeutically effective amount of calcium alpha-ketoglutarate; and (b) a controlled release matrix.

[0011] A composition comprising the unit dose or dosage form of the preceding paragraph, wherein the controlled release matrix comprises hydroxypropyl methylcellulose (HPMC).

[0012] A composition comprising the unit dose and dosage form of any one of the preceding claims, wherein the hydroxypropyl methylcellulose (HPMC) is selected from the group consisting of HPMC having a number average molecular weight of about 22,000 to 30,000, about 68,000 to 95,000, about 115,000 to 150,000, about 220,000 to 300,000, and combinations thereof.

[0013] 10. A composition comprising the unit dose and dosage form of any one of the preceding claims, wherein the controlled release matrix comprises HPMC having a number average molecular weight of about 68,000 to 95,000.

[0014] 10. A composition comprising the unit dose and dosage form of any one of the preceding claims, wherein the controlled release matrix comprises HPMC having a number average molecular weight of about 115,000 to 150,000.

[0015] 10. A composition comprising the unit dose and dosage form of any one of the preceding claims, wherein the controlled release matrix comprises HPMC having a number average molecular weight of about 68,000 to 95,000 and about 115,000 to 150,000.

[0016] A composition comprising the unit dose and dosage form of any one of the preceding claims, wherein the amount of calcium alpha-ketoglutarate is from about 30% to about 65% by total weight of the composition; from about 40% to about 65% by total weight of the composition; from about 40% to about 60% by total weight of the composition; or from about 45% to about 55% by total weight of the composition.

[0017] 10. A composition comprising the unit dose and dosage form of any one of the preceding claims, wherein the amount of calcium alpha-ketoglutarate is about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, or about 65% of the total weight of the composition.

[0018] 2. A composition comprising the unit dose and dosage form of any one of the preceding claims, comprising about 250 to about 1000 mg of calcium alpha-ketoglutarate; about 350 to about 1000 mg of calcium alpha-ketoglutarate; about 400 to about 1000 mg of calcium alpha-ketoglutarate; about 400 to about 900 mg of calcium alpha-ketoglutarate; about 400 to about 800 mg of calcium alpha-ketoglutarate; about 400 to about 700 mg of calcium alpha-ketoglutarate; or about 400 to about 600 mg of calcium alpha-ketoglutarate.

[0019] 10. A composition comprising the unit dose and dosage form of any one of the preceding claims, comprising about 400 mg of calcium alpha-ketoglutarate, about 425 mg of calcium alpha-ketoglutarate, about 450 mg of calcium alpha-ketoglutarate, about 500 mg of calcium alpha-ketoglutarate, about 525 mg of calcium alpha-ketoglutarate, about 550 mg of calcium alpha-ketoglutarate, about 575 mg of calcium alpha-ketoglutarate, or about 600 mg of calcium alpha-ketoglutarate.

[0020] A composition comprising the unit dose and dosage form described in any one of the preceding claims, comprising 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; or about 20% dietary value of calcium.

[0021] A composition comprising a unit dosage and a dosage form as described in any one of the preceding items, further comprising one or more excipients selected from the group consisting of one or more diluents, fillers, disintegrants, lubricants, binders, and suspending agents, and combinations thereof.

[0022] A composition comprising a unit dosage and a dosage form as described in any one of the preceding items, further comprising microcrystalline cellulose, wherein the amount of microcrystalline cellulose is about 14% to about 27% of the total weight of the composition, about 17% to about 23% of the total weight of the composition, about 17% to about 22% of the total weight of the composition, or about 17% to about 20% by weight of the total weight of the composition.

[0023] A composition comprising a unit dosage and a dosage form as described in any one of the preceding items, further comprising lactose monohydrate, wherein the amount of lactose monohydrate is about 6% to about 19% of the total weight of the composition, about 8% to about 17% of the total weight of the composition, about 10% to about 15% of the total weight of the composition, or about 11% to about 14% of the total weight of the composition.

[0024] A composition comprising a unit dosage and a dosage form as described in any one of the preceding items, further comprising one or more lubricants, wherein the lubricant is magnesium stearate, and the amount of magnesium stearate is about 1% to about 5% of the total weight of the composition, about 1% to about 3% of the total weight of the composition, or about 2% to about 4% of the total weight of the composition.

[0025] A composition comprising a unit dosage and a dosage form as described in any one of the preceding items, further comprising one or more disintegrants, wherein the disintegrant is silicon dioxide, and the amount of silicon dioxide is about 1% to about 5% of the total weight of the composition, about 1% to about 3% of the total weight of the composition, or about 2% to about 4% of the total weight of the composition.

[0026] A composition comprising a unit dosage and a dosage form as described in any one of the preceding items, further comprising a sweetener, wherein the sweetener is isomalt.

[0027] 10. Compositions, including unit doses and dosage forms, according to any one of the preceding claims, further comprising a wax, wherein the wax is carnauba wax and / or rice bran wax.

[0028] A composition comprising the unit dose and dosage form of any one of the preceding claims, further comprising one or more agents selected from the group consisting of surfactants, preservatives, flavoring agents, vitamins, antioxidants, and sweeteners.

[0029] 10. A composition, including the unit dose and dosage form of any preceding claim, further comprising one or more vitamins or analogs or derivatives thereof, wherein the vitamin is nicotinamide riboside (NR) and the vitamin is nicotinamide mononucleotide (NMN).

[0030] Compositions, including unit doses and dosage forms according to any one of the preceding claims, further comprising an antioxidant, wherein the antioxidant is fisetin.

[0031] 10. A composition comprising the unit doses and dosage forms of any one of the preceding claims, wherein the release rate of calcium alpha-ketoglutarate is about 90% or less of that of calcium alpha-ketoglutarate compositions formulated without a controlled or controlled release matrix; about 70% or less of that of calcium alpha-ketoglutarate compositions formulated without a controlled or controlled release matrix; about 60% or less of that of calcium alpha-ketoglutarate compositions formulated without a controlled or controlled release matrix; or about 90% or less of that of calcium alpha-ketoglutarate compositions formulated without a controlled or controlled release matrix. 50% or less of the calcium alpha-ketoglutaric acid release rate of a calcium alpha-ketoglutaric acid composition formulated without a controlled release matrix; 40% or less of the calcium alpha-ketoglutaric acid release rate of a calcium alpha-ketoglutaric acid composition formulated without a controlled release matrix; 45% or less of the calcium alpha-ketoglutaric acid release rate of a calcium alpha-ketoglutaric acid composition formulated without a controlled release matrix; or 30% or less of the calcium alpha-ketoglutaric acid release rate of a calcium alpha-ketoglutaric acid composition formulated without a controlled release matrix.

[0032] A composition comprising the unit dose and dosage form of any one of the preceding claims, wherein the dissolution rate is about 30% or less after about 0.5 to about 2 hours in a dissolution medium of 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C as measured by a paddle apparatus with a basket rotating at 75 rpm; less than about 25% after about 0.5 to about 1.5 hours in dissolution medium; less than about 25% after about 1 hour in dissolution medium that is 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C as measured by a paddle apparatus with a basket rotating at 75 rpm; less than about 20% after about 1 hour in dissolution medium that is 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C as measured by a paddle apparatus with a basket rotating at 75 rpm less than about 60% after about 4 to about 8 hours in 900 mL of dissolution medium that is about 0.03 M NaCl and about 0.08 M HCl at about 37°C as measured by a paddle apparatus with a basket rotating at 75 rpm; less than about 60% after about 8 hours in 900 mL of dissolution medium that is about 0.03 M NaCl and about 0.08 M HCl at about 37°C as measured by a paddle apparatus with a basket rotating at 75 rpm; 1. The composition of claim 1, wherein the composition has a calcium alpha-ketoglutarate release rate of about 60% or less after about 4 to about 6 hours in 900 mL of dissolution medium that is about 0.03 M NaCl and about 0.08 M HCl at about 37° C. as measured by a paddle apparatus equipped with a basket; and about 60% or less after about 6 hours in 900 mL of dissolution medium that is about 0.03 M NaCl and about 0.08 M HCl at about 37° C. as measured by a paddle apparatus equipped with a basket rotating at 75 rpm.

[0033] 10. A composition comprising the unit dose and dosage form of any one of the preceding claims, wherein the dissolution rate is greater than about 75% after about 10 to about 11 hours in 900 mL of dissolution medium that is about 0.03 M NaCl and about 0.08 M HCl at about 37°C as measured by a paddle apparatus with a basket rotating at 75 rpm; or greater than about 75% after about 10 to about 11 hours in 900 mL of dissolution medium that is about 0.03 M NaCl and about 0.08 M HCl at about 37°C as measured by a paddle apparatus with a basket rotating at 75 rpm. greater than about 75% after about 10 hours in the body; greater than about 75% after about 9 to about 11 hours in a dissolution medium that is 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C as measured by a paddle apparatus with a basket rotating at 75 rpm; greater than about 75% after about 9 hours in a dissolution medium that is 900 mL of about 0.03 M NaCl and about 0.08 M HCl at about 37°C as measured by a paddle apparatus with a basket rotating at 75 rpm; greater than about 90% after about 12 to about 15 hours in 900 mL of dissolution medium that is about 0.03 M NaCl and about 0.08 M HCl at about 37°C as measured by a paddle apparatus with a basket rotating at 75 rpm; greater than about 90% after about 12 to about 14 hours in 900 mL of dissolution medium that is about 0.03 M NaCl and about 0.08 M HCl at about 37°C as measured by a paddle apparatus with a basket rotating at 75 rpm A composition characterized by a calcium alpha-ketoglutarate release rate of about 90% or greater after about 13 hours in 900 mL of a dissolution medium that is about 0.03 M NaCl and about 0.08 M HCl at about 37° C. as measured by a paddle apparatus; or about 90% or greater after about 12 hours in 900 mL of a dissolution medium that is about 0.03 M NaCl and about 0.08 M HCl at about 37° C. as measured by a paddle apparatus with a basket rotating at 75 rpm.

[0034] A composition comprising the unit dose and dosage form of any one of the preceding claims, wherein the calcium alpha-ketoglutarate is calcium alpha-ketoglutarate monohydrate.

[0035] A composition comprising the unit dose and dosage form of any one of the preceding claims, comprising 525 mg of calcium alpha-ketoglutarate monohydrate.

[0036] A composition comprising a unit dose and dosage form according to any one of the preceding claims, wherein the dosage unit is configured for oral administration, the dosage unit is a tablet, and the dosage unit is a capsule.

[0037] A unit dose comprising 525 mg of Ca-AKG monohydrate and a controlled release matrix, isomalt, one or more vegetable waxes, stearic acid, magnesium stearate, silica, wherein the controlled release matrix comprises HPMC.

[0038] The unit dose of any one of the preceding claims, further comprising a coating as described herein.

[0039] The pharmacological treatment and prevention of the natural decline of aging and age-related diseases presents a challenge to the medical community, in part due to the stringent properties required of drugs for this purpose. The elderly patient population places an unusually high burden on pharmacological therapies that are bioavailable, non-toxic, and free of long-term side effects. Prevention requires the treatment of patients who may be at risk for age-related disorders but who are experiencing no or mild symptoms, and requires agents that do not impair existing health. Treatment of patients with existing age-related diseases imposes high requirements for non-toxicity so as not to worsen existing health conditions. Furthermore, treatment or prevention of age-related disorders generally likely requires drug treatment over many years, and therefore such agents must not have cumulative toxicity or long-term adverse effects on organ systems.

[0040] Recent discoveries suggest that aging is driven by molecular programs operating in animals, and not simply by the accumulation of molecular damage. Studies in humans and model organisms aimed at elucidating the molecular mechanisms of aging have shown the existence of widely conserved longevity pathways. Various studies have shown that dietary restriction, fasting, or calorie restriction can extend lifespan and delay the onset of multiple age-related phenotypes in a wide range of organisms, including all of the major model systems described herein.

[0041] The mTOR signaling pathway has emerged as a central aging-promoting pathway, particularly one that is inhibited due to the pro-longevity effects of dietary restriction in yeast, nematodes, and Drosophila. In response to nutrient depletion, mTOR activity is reduced, leading to downstream events that have been shown to promote lifespan extension through activation of changes in gene transcription and protein translation, and altered regulation of mTOR substrates by phosphorylation, and to improve resistance to environmental stressors. Furthermore, dietary restriction is known to have effects not only on mTOR but also on other aging processes, including the AMPK pathway (activation), the sirtuin pathway (increased protein levels), mitochondrial bioenergetics (activation), and the IGF-1 pathway (inhibition).

[0042] In some embodiments, Ca-AKG regulates the mTOR pathway. In some embodiments, Ca-AKG regulates the AMPK pathway. In some embodiments, Ca-AKG regulates the mTOR pathway and the AMPK pathway.

[0043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used to practice or test the present invention, suitable methods and materials are described below. In case of conflict, the present patent specification, including definitions, will prevail. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0044] As used herein, the singular includes the plural unless specifically stated otherwise. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless specifically stated otherwise. Furthermore, the use of the term "including" and other forms such as "include," "includes," "included," etc., is not limiting.

[0045] "Alpha-ketoglutarate," "α-ketoglutarate," or "AKG" includes derivatives of alpha-ketoglutarate (e.g., those described in MacKenzie et al., (2007) Mol Cell Biol 27(9):3282-3289), analogs of alpha-ketoglutarate (e.g., phosphonate analogs (e.g., those cited in Bunik et al., (2005) Biochemistry 44(31):10552-61)), esters of alpha-ketoglutarate (e.g., dimethyl alpha-ketoglutarate and octyl alpha-ketoglutarate), and various species-specific analogs, such as human alpha-ketoglutarate, porcine alpha-ketoglutarate, mouse alpha-ketoglutarate, bovine alpha-ketoglutarate, etc.

[0046] As used herein, the terms "individual(s)," "subject(s)," and "patient(s)" refer to any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. None of the terms require or are limited to situations characterized by the supervision (e.g., continuous or intermittent) of a medical professional (e.g., a physician, registered nurse, nurse practitioner, physician's assistant, hospital worker, or hospice worker).

[0047] As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes the exact amount. Thus, "about 5 μL" means "about 5 μL" and "5 μL." In general, the term "about" includes amounts that are expected to be within experimental error.

[0048] The terms "controlled-release dosage form" and "controlled-release layer" are used interchangeably and are defined as those in which the time course and / or location of drug release characteristics are selected to achieve a therapeutic or convenient goal not provided by conventional immediate-release dosage forms. The release rate of an active drug from a controlled-release layer or controlled-release dosage form is controlled not only by physiological or environmental conditions, but also by the characteristics of the dosage form and / or in combination with physiological or environmental conditions. Controlled-release dosage forms are used to maintain drug plasma levels within a therapeutic window. Certain embodiments of controlled-release dosage forms attempt to deliver a therapeutically effective amount of an active drug as a once-daily dose such that the Cmax / Cmin ratio in plasma at steady state is less than the therapeutic index, and to maintain drug levels at a constant, effective level to provide therapeutic benefit over a period of time (e.g., 24 hours). In certain embodiments, controlled-release dosage forms provide a substantially constant or gradually decreasing drug release rate to provide plasma levels that remain substantially unchanged over time. In certain embodiments, the controlled-release dosage form is designed to provide a rapid increase in the plasma concentration of the drug that remains substantially constant within the therapeutic range of the drug for a period of time (e.g., 24 hours). Alternatively, in some other embodiments, the controlled-release dosage form is designed to provide a rapid increase in the plasma concentration of the drug, which may not remain constant, but declines at a rate such that the plasma concentration remains within the therapeutic range for a period of time (e.g., 24 hours).

[0049] The term "controlled-release matrix" refers to a matrix, such as a polymeric matrix, that can deliver a bioactive agent at a controlled rate over a period of time. While there may be an initial burst phase, the overall release kinetics of the bioactive agent from the matrix is ​​generally linear, such that a relatively constant supply of bioactive agent is released over a desired period of time. The period can vary from hours to days, depending on the bioactive agent and its intended use. Generally, it is preferred that the percentage of bioactive agent released from a controlled matrix over the treatment period be relatively high (e.g., at least about 50%, at least about 75%, at least about 90%, or at least about 95%) to avoid wasting unreleased bioactive agent. As used herein, the term "release modifier" generally refers to a component that, individually or together, forms at least a portion of a controlled-release matrix.

[0050] The term "immediate release" layer or dosage form refers to the release of an active agent substantially immediately after administration. For example, immediate release includes, but is not limited to, contact with gastric fluid, resulting in substantially complete dissolution within about 1 hour. An immediate release component may also be referred to as instantaneous release. When used in connection with the dissolution profile discussed herein, the term "immediate release" refers to the portion of the dosage form disclosed herein that delivers an active agent for a period of less than 1 hour.

[0051] 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 used to create a controlled-release coating. The coating composition is applied to the calcium alpha-ketoglutarate core to form an intermediate coating, which is cured to form the controlled-release coating.

[0052] The terms "effective amount," "pharmacologically effective amount," or "therapeutically effective amount" refer to a non-toxic but sufficient amount of an agent to provide a desired biological, therapeutic, and / or prophylactic result. That 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 alpha-ketoglutarate disclosed herein itself, or a composition comprising calcium alpha-ketoglutarate disclosed herein, required to produce a clinically significant reduction in a disease or condition. The appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0053] As used herein, the term "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesired biological effects or interacting in a deleterious manner with any of the components of the composition contained therein.

[0054] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent consisting of the cationic form of the therapeutically active agent in combination with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCR 2002. S.M. Berge, L.D.Bighley, D.C. Monkhouse, J.Pharm.Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble and dissolve faster in gastric and intestinal fluids than non-ionic species, making them useful in solid dosage forms. Furthermore, their solubility is often a function of pH, allowing for selective dissolution in one part of the gastrointestinal tract or another, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Also, salt-forming molecules can be in equilibrium with neutral forms, allowing for tailored passage through biological membranes.

[0055] As used herein, "treatment" or "treating" refers to an approach to obtaining a beneficial or desired result with respect to a disease, disorder, or condition, including, but not limited to, therapeutic benefit and / or preventative benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated. Therapeutic benefit is also achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disease, such that an improvement is observed in the subject, even though the subject may still be suffering from the underlying disease. In certain embodiments, for preventative benefit, the composition is administered to a subject at risk of developing a particular disease or who has reported one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0056] A "therapeutic effect," as that term is used herein, encompasses the therapeutic and / or prophylactic benefits described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0057] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, lubricant, sweetener, diluent, preservative, dye, colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent that is approved by the United States Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0058] Alpha-ketoglutarate (AKG) Described herein are sustained release compositions of alpha-ketoglutarate.

[0059] In certain aspects, the present disclosure provides compositions comprising compounds (e.g., salts of alpha-ketoglutarate) that are available for human consumption without FDA approval or that are generally recognized as safe (GRAS). Such compounds can be classified as such because they a) are present in the FDA SCOGS database and are generally recognized as safe by the U.S. Food and Drug Administration, or b) are derived from plants (e.g., fruits, vegetables, herbs) present in traditional diets and are therefore recognized by the scientific community as safe for consumption. In some embodiments, GRAS compounds are compounds that are available for human consumption without FDA approval.

[0060] In some embodiments, the compositions disclosed herein contain AKG. Alpha-ketoglutarate or α-ketoglutarate (Formula 1) is also known as 2-oxopentanedioic acid, 2-ketoglutaric acid, 2-oxoglutaric acid, and oxoglutaric acid. At physiological pH, α-ketoglutarate exists in one or more deprotonated forms, such as that shown in Formula 2. Alpha-ketoglutarate is an intermediate in the Krebs cycle of eukaryotic organisms and is biosynthesized in such organisms from the isocitrate cycle (Krebs cycle process) or L-glutamate (via alanine transaminase). Both α-ketoglutarate and its corresponding salts are commercially available either through preparation from fermentation cultures (see, for example, U.S. Pat. No. 2,776,926) or chemical synthesis from closely related compounds. [ka]

[0061] Consistent with its role in energy generation via the Krebs cycle, α-ketoglutarate is a key regulator of intracellular bioenergetics, implicated as an inhibitor of ATP synthase subunit β and an indirect inhibitor of the kinase mTOR, resulting from partial inhibition of the mitochondrial electron transport chain.

[0062] In some embodiments, α-ketoglutarate is provided as the free acid (α-ketoglutaric acid). In some embodiments, α-ketoglutarate is provided as a mono- or bis-salt. In other embodiments, α-ketoglutarate is provided as a monosodium salt, disodium salt, monopotassium salt, or dipotassium salt. In yet other embodiments, α-ketoglutarate is provided as a monovalent or divalent salt with other cations listed in the USFDA Orange Book. Such cations include calcium, diolamine, lithium, lysine, magnesium, meglumine, olamine, tromethamine, and zinc. In further embodiments, the α-ketoglutarate salt is provided as an anhydrous salt, hemihydrate, monohydrate, or dihydrate.

[0063] Further disclosed herein, in certain aspects, are compositions comprising a salt of α-ketoglutarate. In some embodiments, the α-ketoglutarate is provided as a calcium salt (Ca-AKG). In some embodiments, the calcium α-ketoglutarate can be calcium α-ketoglutarate hydrate. In some embodiments, the calcium α-ketoglutarate can be calcium α-ketoglutarate monohydrate. In some embodiments, the calcium α-ketoglutarate can be calcium α-ketoglutarate hemihydrate. In some embodiments, the calcium α-ketoglutarate can be calcium α-ketoglutarate anhydrous.

[0064] In some embodiments, the compositions disclosed herein comprise an ester of α-ketoglutarate. In some embodiments, the ester of α-ketoglutarate is the methyl ester of α-ketoglutarate. In some embodiments, the ester of α-ketoglutarate is the dimethyl ester of α-ketoglutarate. In some embodiments, the ester of α-ketoglutarate is the ethyl ester of α-ketoglutarate. In some embodiments, the ester of α-ketoglutarate is the diethyl ester of α-ketoglutarate.

[0065] In some embodiments, alpha-ketoglutarate is provided as a monolithium salt, dilithium salt, monosodium salt, disodium salt, monopotassium salt, dipotassium salt, calcium salt, or zinc salt. In some embodiments, alpha-ketoglutarate is provided as a calcium salt. In further embodiments, the calcium salt of alpha-ketoglutarate is provided as an anhydrous salt, monohydrate, or dihydrate. In further embodiments, alpha-ketoglutarate is provided as a monovalent or divalent salt with other cations listed in the U.S. Food and Drug Administration Orange Book. Such cations include calcium, diolamine, lithium, lysine, magnesium, meglumine, olamine, tromethamine, and zinc.

[0066] Sustained release compositions of alpha-ketoglutarate In one aspect, described herein are compositions comprising a therapeutically effective amount of calcium alpha-ketoglutarate and a controlled-release matrix, wherein the compositions are characterized by, capable of, or configured to provide a calcium alpha-ketoglutarate release rate over or during a predetermined period of time that is no more than 90% of the calcium alpha-ketoglutarate release rate of one or more calcium alpha-ketoglutarate compositions formulated without any controlled-release matrix.

[0067] In some embodiments, the compositions provide a release rate of calcium alpha-ketoglutarate that is 80% or less than the release rate of calcium alpha-ketoglutarate compositions formulated without any controlled-release matrix. In some embodiments, the compositions provide a release rate of calcium alpha-ketoglutarate that is 70% or less than the release rate of calcium alpha-ketoglutarate compositions formulated without any controlled-release matrix. In some embodiments, the compositions provide a release rate of calcium alpha-ketoglutarate that is 60% or less than the release rate of calcium alpha-ketoglutarate compositions formulated without any controlled-release matrix. In some embodiments, the compositions provide a release rate of calcium alpha-ketoglutarate that is 50% or less than the release rate of calcium alpha-ketoglutarate compositions formulated without any controlled-release matrix. In some embodiments, the compositions provide a release rate of calcium alpha-ketoglutarate that is 40% or less than the release rate of calcium alpha-ketoglutarate compositions formulated without any controlled-release matrix. In some embodiments, the compositions provide a release rate of calcium alpha-ketoglutarate that is 30% or less than the release rate of calcium alpha-ketoglutarate compositions formulated without any controlled-release matrix. In some embodiments, the compositions provide a release rate of calcium alpha-ketoglutarate that is 20% or less than the release rate of calcium alpha-ketoglutarate compositions formulated without any controlled-release matrix. In some embodiments, the compositions provide a release rate of calcium alpha-ketoglutarate that is 10% or less than the release rate of calcium alpha-ketoglutarate compositions formulated without any controlled-release matrix.In some embodiments, the compositions provide a calcium alpha-ketoglutarate release rate that is 5% or less of the calcium alpha-ketoglutarate release rate of a calcium alpha-ketoglutarate composition formulated without any controlled release matrix.

[0068] Amount of Calcium Alpha-Ketoglutarate In some embodiments, the amount of calcium alpha-ketoglutarate is 15% to 85% by weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is 15% to 75% by weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is 30% to 70% by weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is 40% to 70% by weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is 30% to 65% by weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is 40% to 65% by weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is 30% to 60% by weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is 40% to 60% by weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is 45% to 55% by weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is 45%-52% by total weight of the composition, hi some embodiments, the amount of calcium alpha-ketoglutarate is 46%-53% by total weight of the composition.

[0069] In some embodiments, the amount of calcium alpha-ketoglutarate in the composition corresponds to about 10% w / w to about 75% w / w of the total weight of the composition. In other embodiments, the amount of calcium alpha-ketoglutarate is 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, or about 44% w / w of the total weight of the composition. / 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 63% w / 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 about 75% w / w.

[0070] In some embodiments, the amount of calcium alpha-ketoglutarate is about 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65% of the total weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is about 30% of the total weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is about 35% of the total weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is about 40% of the total weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is about 45% of the total weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is about 50% of the total weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is about 55% of the total weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is about 60% of the total weight of the composition. In some embodiments, the amount of calcium alpha-ketoglutarate is about 65% of the total weight of the composition.

[0071] Controlled Release Matrix 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 of about 68,000-95,000. In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight of about 115,000-150,000. In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight of about 65,000-102,000 and about 103,000-156,000. In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight of about 68,000 to 95,000 and 115,000 to 150,000. In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight of about 77,000 to 95,000 and about 109,000 to 128,000.

[0072] In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight of about 18,000 to 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 up to 44,000. In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight of 18,000 to 20,000, 18,000 to 23,000, 18,000 to 27,000, 18,000 to 30,000, 18,000 to 33,000, 18,000 to 36,000, 18,000 to 39,000, 18,000 to 41,000, 18,000 to 44,000, 20,000 to 23,000, 20,000 to 35,000, 25,000 to 36,000, 26,000 to 39,000, 27,000, 28,000 to 30,000, 29,000 to 35,000, 30,000 to 36,000, 31,000 to 39,000, 32,000 to 41,000, 33,000, 34,000, 35,000, 36,000, 37,000, 38,000, 39,000, 40,000, 41,000, 42,000, 43,000, 44,000, 45,00 00~27,000, 20,000~30,000, 20,000~33,000, 20,000~36,000, 20,000~39,000, 20,000~41,000, 20,000~44,000, 23,000~27,000, 23,000~30,000, 23,000~33,000, 23,000~36,000, 23,000~39,000, 23,00 0-41,000, 23,000-44,000, 27,000-30,000, 27,000-33,000, 27,000-36,000, 27,000-39,000, 27,000-41,000, 27,000-44,000, 30,000-33,000, 30,000-36,000, 30,000-39,000, 30,000-41,000, 30,000 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.

[0073] In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight of about 65,000 to 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 has an RI of 65,000 to 68,000, 65,000 to 71,000, 65,000 to 74,000, 65,000 to 77,000, 65,000 to 80,000, 65,000 to 83,000, 65,000 to 87,000, 65,000 to 91,000, 65,000 to 95,000, 65,000 to 99,000, 65,000 to 102,000, 68,000 to 71,000, 68,000 to 74,000, 68,000 to 77,000, 68,000 to 80,000, 68,000 to 83,000, 000, 68,000-87,000, 68,000-91,000, 68,000-95,000, 68,000-99,000, 68,000-102,000, 71,000-74,000, 71,000-77,000, 71,000-80,000, 71,00 0-83,000, 71,000-87,000, 71,000-91,000, 71,000-95,000, 71,000-99,000, 71,000-102,000, 74,000-77,000, 74,000-80,000, 74,000-83,000, 7 4,000-87,000, 74,000-91,000, 74,000-95,000, 74,000-99,000, 74,000-102,000, 77,000-80,000, 77,000-83,000, 77,000-87,000, 77,000-91, 000, 77,000-95,000, 77,000-99,000, 77,000-102,000, 80,000-83,000, 80,000-87,000, 80,000-91,000, 80,000-95,000, 80,000-99,000, 80,000 and HPMC having a number average molecular weight of 83,000 to 102,000, 83,000 to 87,000, 83,000 to 91,000, 83,000 to 95,000, 83,000 to 99,000, 83,000 to 102,000, 87,000 to 91,000, 87,000 to 95,000, 87,000 to 99,000, 87,000 to 102,000, 91,000 to 95,000, 91,000 to 99,000, 91,000 to 102,000, 95,000 to 99,000, 95,000 to 102,000, or 99,000 to 102,000.In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight of 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.

[0074] In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight of about 103,000 to 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 has a saturation of 103,000 to 109,000, 103,000 to 115,000, 103,000 to 118,000, 103,000 to 123,000, 103,000 to 128,000, 103,000 to 133,000, 103,000 to 138,000, 103,000 to 142,000, 103,000 to 146,000, 103,000 to 150,000, 103,000 to 156,000, 109,000 ~115,000, 109,000~118,000, 109,000~123,000, 109,000~128,000, 109,000~133,000, 109,000~138,000, 109,000~142,000, 109,000~146,000, 109,000~150,000, 109,000~156,000, 115,000~118,000, 115,000~123,000, 115,000~128,000, 115,000 0-133,000, 115,000-138,000, 115,000-142,000, 115,000-146,000, 115,000-150,000, 115,000-156,000, 118,000-123,000, 118,000-128,000, 118,000-133,000, 118,000-138,000, 118,000-142,000, 118,000-146,000, 118,000-150,000, 118,000 00~156,000, 123,000~128,000, 123,000~133,000, 123,000~138,000, 123,000~142,000, 123,000~146,000, 123,000~150,000, 123,000~156,000, 128,000~133,000, 128,000~138,000, 128,000~142,000, 128,000~146,000, 128,000~150,000, 128,000~156,000, 133,000~138,000, 133,000~142,000, 133,000~146,000, 133,000~150,000, 133,000~156,000, 138,000~142,000, 138,000~146,000, 138,000~150, In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight of 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.

[0075] In some embodiments, the controlled-release matrix comprises HPMC having a number average molecular weight of about 170,000 to 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 has a saturation of 170,000 to 180,000, 170,000 to 190,000, 170,000 to 200,000, 170,000 to 210,000, 170,000 to 220,000, 170,000 to 230,000, 170,000 to 240,000, 170,000 to 260,000, 170,000 to 280,000, 170,000 to 300,000, 170,000 to 320,000, 180,000 ~190,000, 180,000~200,000, 180,000~210,000, 180,000~220,000, 180,000~230,000, 180,000~240,000, 180,000~260,000, 180,000~280,000, 180,000~300,000, 180,000~320,000, 190,000~200,000, 190,000~210,000, 190,000~220,000, 190,000 0~230,000, 190,000~240,000, 190,000~260,000, 190,000~280,000, 190,000~300,000, 190,000~320,000, 200,000~210,000, 200,000~220,000, 200,000~230,000, 200,000~240,000, 200,000~260,000, 200,000~280,000, 200,000~300,000, 200,0 00~320,000, 210,000~220,000, 210,000~230,000, 210,000~240,000, 210,000~260,000, 210,000~280,000, 210,000~300,000, 210,000~320,000, 220,000~230,000, 220,000~240,000, 220,000~260,000, 220,000~280,000, 220,000~300,000, 220,000~320,000, 230,000~240,000, 230,000~260,000, 230,000~280,000, 230,000~300,000, 230,000~320,000, 240,000~260,000, 240,000~280,000, 240,000~300, In some embodiments, the controlled release matrix comprises HPMC having a number average molecular weight of 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.

[0076] release rate In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 30% or less in 0.5 to 2 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0077] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 25% or less in 0.5 to 2 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0078] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 25% or less in 0.5 to 1.5 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0079] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 20% or less in 0.5 to 1.5 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0080] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 30% or less in 1 hour in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0081] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 25% or less in 1 hour in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0082] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 20% or less in 1 hour in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0083] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 19% or less in 1 hour in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0084] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 18% or less in 1 hour in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0085] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 17% or less in 1 hour in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0086] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 16% or less in 1 hour in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0087] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 15% or less in 1 hour in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0088] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 60% or less in 4-8 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0089] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 60% or less in 4-6 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0090] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 60% or less in 8 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0091] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 60% or less in 7 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0092] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 60% or less in 6 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0093] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 60% or less in 5 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0094] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 55% or less in 5 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0095] In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 50% or less in 5 hours in a dissolution medium as measured by a paddle apparatus, and a release rate of ketoglutarate of 45% or less in 5 hours in a dissolution medium as measured by a paddle apparatus with a basket rotating at 75 rpm, wherein the dissolution medium is 900 mL of 0.03 M NaCl and 0.08 M HCl at about 37° C.

[0096] In some embodiments, the composition provides a calcium alpha-ketoglutarate release rate of 50% or less in 4 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 45% or less in 4 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 40% or less in 4 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 75% or greater in 9-11 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 75% or greater in 9-10 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 75% or greater in 10-11 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of about 75% or greater in about 9 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of about 75% or greater in about 10 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of about 75% or greater in about 11 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 90% or greater in 11-15 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 90% or greater in 11-14 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 90% or greater in 11-13 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 90% or greater in 11-12 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 90% or greater in 12-15 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of about 90% or greater in 12-14 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of about 90% or greater in 12-13 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 90% or greater in 11 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 90% or greater in 12 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 90% or greater in 13 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition provides a calcium alpha-ketoglutarate release rate of 90% or greater in 14 hours in a dissolution medium, as measured by a paddle apparatus with a basket rotating at 75 rpm, 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, the composition comprises one or more excipients.

[0117] In some embodiments, the excipient is selected from the group consisting of a diluent, a filler, a disintegrant, a lubricant, a binder, a suspending agent, and combinations thereof.

[0118] In some embodiments, the excipient is selected from the group consisting of a diluent, a filler, a disintegrant, a lubricant, and combinations thereof.

[0119] In some embodiments, the composition includes a first diluent. In some embodiments, the amount of the first diluent is 11% to 29% of the total weight of the composition. In some embodiments, the amount of the first diluent is at least 11% of the total weight of the composition. In some embodiments, the amount of the first diluent is at most 29% of the total weight of the composition. In some embodiments, the amount of first diluent is between 11% and 14%, 11% and 17%, 11% and 19%, 11% and 20%, 11% and 21%, 11% and 23%, 11% and 25%, 11% and 27%, 11% and 29%, 14% and 17%, 14% and 19%, 14% and 20%, 14% and 21%, 14% and 23%, 14% and 25%, 14% and 27%, 14% and 29%, 17% and 19%, 17% and 20%, 17% and 21%, 17% and 23%, 17%-25%, 17%-27%, 17%-29%, 19%-20%, 19%-21%, 19%-23%, 19%-25%, 19%-27%, 19%-29%, 20%-21%, 20%-23%, 20%-25%, 20%-27%, 20%-29%, 21%-23%, 21%-25%, 21%-27%, 21%-29%, 23%-25%, 23%-27%, 23%-29%, 25%-27%, 25%-29%, or 27%-29%. 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% of the total weight of the composition.

[0120] In some embodiments, the first diluent is microcrystalline cellulose. In some embodiments, the amount of microcrystalline cellulose is 11% to 29% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is 14% to 27% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is 17% to 23% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is 17% to 22% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is 17% to 20% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is at least 11% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is at most 29% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is between 11% and 14%, 11% and 17%, 11% and 19%, 11% and 20%, 11% and 21%, 11% and 23%, 11% and 25%, 11% and 27%, 11% and 29%, 14% and 17%, 14% and 19%, 14% and 20%, 14% and 21%, 14% and 23%, 14% and 25%, 14% and 27%, 14% and 29%, 17% and 19%, 17% and 20%, 17% and 21%, 17% and 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%. 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 weight of the total composition. In some embodiments, the amount of microcrystalline cellulose is about 19% by weight of the total composition. In some embodiments, the amount of microcrystalline cellulose is about 20% by weight of the total composition. In some embodiments, the amount of microcrystalline cellulose is about 21% by weight of the total composition.In some embodiments, the amount of microcrystalline cellulose is about 23% by weight of the total composition. In some embodiments, the amount of microcrystalline cellulose is about 25% by weight of the total composition. In some embodiments, the amount of microcrystalline cellulose is about 27% by weight of the total composition. In some embodiments, the amount of microcrystalline cellulose is about 29% by weight of the total composition.

[0121] In some embodiments, the composition includes a second diluent. In some embodiments, the amount of the second diluent is 4% to 19% by weight of the total composition. In some embodiments, the amount of the second diluent is at least 4% by weight of the total composition. In some embodiments, the amount of lactose monohydrate is at most 19% by weight of the total composition. In some embodiments, the amount of second diluent is between 4% and 6%, 4% and 8%, 4% and 10%, 4% and 11%, 4% and 12%, 4% and 13%, 4% and 14%, 4% and 15%, 4% and 17%, 4% and 19%, 6% and 8%, 6% and 10%, 6% and 11%, 6% and 12%, 6% and 13%, 6% and 14%, 6% and 15%, 6% and 17%, 6% and 19%, 8% and 10%, 8% and 11%, 8% and 12%, 8% and 13%, 8% and 14%, 8% and 15%, 8% and 17%, 8% and 19%, 10% and 11% of the total weight of the composition. , 10%-12%, 10%-13%, 10%-14%, 10%-15%, 10%-17%, 10%-19%, 11%-12%, 11%-13%, 11%-14%, 11%-15%, 11%-17%, 11%-19%, 12%-13%, 12%-14%, 12%-15%, 12%-17%, 12%-19%, 13%-14%, 13%-15%, 13%-17%, 13%-19%, 14%-15%, 14%-17%, 14%-19%, 15%-17%, 15%-19%, or 17%-19%. 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% of the total weight of the composition.

[0122] In some embodiments, the second diluent is lactose monohydrate. In some embodiments, the amount of lactose monohydrate is 4% to 19% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is 6% to 19% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is 8% to 17% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is 10% to 15% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is 11% to 14% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is at least 4% by weight of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is at most 19% by weight of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is between 4% and 6%, 4% and 8%, 4% and 10%, 4% and 11%, 4% and 12%, 4% and 13%, 4% and 14%, 4% and 15%, 4% and 17%, 4% and 19%, 6% and 8%, 6% and 10%, 6% and 11%, 6% and 12%, 6% and 13%, 6% and 14%, 6% and 15%, 6% and 17%, 6% and 19%, 8% and 10%, 8% and 11%, 8% and 12%, 8% and 13%, 8% and 14%, 8% and 15%, 8% and 17%, 8% and 19%, 10% and 14% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 4% by weight of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 6% by weight of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 8% by weight of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 10% by weight of the total weight of the composition.In some embodiments, the amount of lactose monohydrate is about 11% by weight of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 12% by weight of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 13% by weight of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 14% by weight of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 15% by weight of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 17% by weight of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 19% by weight of the total weight of the composition.

[0123] In some embodiments, the composition includes a lubricant. In some embodiments, the amount of lubricant is 1% to 5% of the total weight of the composition. In some embodiments, the amount of lubricant is at least 1% by weight of the total weight of the composition. In some embodiments, the amount of lubricant is up to 5% of the total weight of the composition. In some embodiments, the amount of 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% of the total weight of the composition. In some embodiments, the amount of lubricant is 1%, 2%, 3%, 4%, or 5% of the total weight of the composition.

[0124] In some embodiments, the lubricant is magnesium stearate. In some embodiments, the amount of magnesium stearate is 1%-5% of the total weight of the composition. In some embodiments, the amount of magnesium stearate is 1%-3% of the total weight of the composition. In some embodiments, the amount of magnesium stearate is 2%-4% of the total weight of the composition. In some embodiments, the amount of magnesium stearate is at least 1% of the total weight of the composition. In some embodiments, the amount of magnesium stearate is up to 5% of the total weight of the composition. In some embodiments, the amount of magnesium stearate is 1%-2%, 1%-3%, 1%-4%, 1%-5%, 2%-3%, 2%-4%, 2%-5%, 3%-4%, 3%-5%, or 4%-5% of the total weight of the composition. In some embodiments, the amount of magnesium stearate is 1%, 2%, 3%, 4%, or 5% of the total weight of the composition.

[0125] In some embodiments, the amount of magnesium stearate is about 1% by weight of the total composition. In some embodiments, the amount of magnesium stearate is about 2% by weight of the total composition. In some embodiments, the amount of magnesium stearate is about 3% by weight of the total composition. In some embodiments, the amount of magnesium stearate is about 4% by weight of the total composition. In some embodiments, the amount of magnesium stearate is about 5% by weight of the total composition.

[0126] In some embodiments, the composition includes a disintegrant. In some embodiments, the amount of disintegrant is 1% to 5% of the total weight of the composition. In some embodiments, the amount of disintegrant is at least 1% of the total weight of the composition. In some embodiments, the amount of disintegrant is at most 5% of the total weight of the composition. In some embodiments, the amount of disintegrant 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% of the total weight of the composition. In some embodiments, the amount of disintegrant is 1%, 2%, 3%, 4%, or 5% of the total weight of the composition.

[0127] In some embodiments, the disintegrant is silicon dioxide. In some embodiments, the amount of silicon dioxide is 1% to 5% of the total weight of the composition. In some embodiments, the amount of silicon dioxide is 1% to 3% of the total weight of the composition. In some embodiments, the amount of silicon dioxide is 2% to 4% of the total weight of the composition. In some embodiments, the amount of silicon dioxide is at least 1% of the total weight of the composition. In some embodiments, the amount of silicon dioxide is up to 5% of the total weight of the composition. In some embodiments, the silicon dioxide 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% of the total weight of the composition.

[0128] In some embodiments, the amount of silicon dioxide is about 1% by weight of the total composition. In some embodiments, the amount of silicon dioxide is about 2% by weight of the total composition. In some embodiments, the amount of silicon dioxide is about 3% by weight of the total composition. In some embodiments, the amount of silicon dioxide is about 4% by weight of the total composition. In some embodiments, the amount of silicon dioxide is about 5% by weight of the total composition.

[0129] Alpha-Ketoglutarate Composition In another aspect, described herein is a composition comprising calcium alpha-ketoglutarate and one or more agents selected from the group consisting of surfactants, preservatives, flavoring agents, vitamins, antioxidants, sweeteners, and combinations thereof.

[0130] In some embodiments, the amount of calcium alpha-ketoglutarate is between 50 mg and 5000 mg. In some embodiments, the amount of calcium alpha-ketoglutarate is between 100 mg and 2000 mg. In some embodiments, the amount of calcium alpha-ketoglutarate is about 250 mg. In some embodiments, the amount of calcium alpha-ketoglutarate is about 500 mg. In some embodiments, the amount of calcium alpha-ketoglutarate is about 525 mg. In some embodiments, the amount of calcium alpha-ketoglutarate is about 550 mg. In some embodiments, the amount of calcium alpha-ketoglutarate is about 750 mg.

[0131] In some embodiments, the calcium alpha-ketoglutarate is calcium alpha-ketoglutarate monohydrate.

[0132] 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 100-3000 mcg; 200 mcg-1000 mcg; about 250 mcg; about 450 mcg; or about 650 mcg. In some embodiments, the vitamin A is retinyl palmitate.

[0133] In some embodiments, the vitamin is vitamin D. In some embodiments, the amount of vitamin D is 50 IU to 3000 IU; 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, the vitamin D is cholecalciferol.

[0134] In some embodiments, the composition further comprises a sweetener, hi some embodiments, the sweetener is isomalt.

[0135] In some embodiments, the composition further comprises a wax, hi some embodiments, the wax is carnauba wax and / or rice bran wax.

[0136] In some embodiments, the composition further comprises one or more excipients. In some embodiments, the excipient is selected from the group consisting of solubilizers, diluents, fillers, disintegrants, glidants, binders, suspending agents, and combinations thereof. In some embodiments, the excipient is selected from the group consisting of solubilizers, diluents, fillers, disintegrants, glidants, glidants, and combinations thereof.

[0137] 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 lubricant. In some embodiments, the lubricant is silica.

[0138] In another aspect, also described herein is a composition comprising calcium alpha-ketoglutarate 500 mg; retinyl palmitate 450 mcg, and further comprising isomalt, vegetable wax (carnauba and / or rice bran), stearic acid, magnesium stearate, and silica.

[0139] In another aspect, also described herein is a composition comprising calcium alpha-ketoglutarate 500 mg; cholecalciferol 12.5 mcg (500 IU), and further comprising isomalt, vegetable wax (carnauba and / or rice bran), stearic acid, magnesium stearate, and silica.

[0140] Controlled-Release Matrix Formulations In certain embodiments, the calcium alpha-ketoglutarate compositions described herein comprise a controlled-release matrix. There are many mechanisms by which a bioactive agent can be released from a controlled-release matrix. Two mechanisms include diffusion and / or degradation. Diffusion occurs when the bioactive agent is released through pores within the polymer 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 localized within a reservoir adjacent to or within the matrix. In a reservoir system, a reservoir of bioactive agent within the polymer matrix, e.g., a solid drug, a dilute solution, or a concentrated drug solution, is surrounded by a controlled-release material through which the bioactive agent can diffuse. In a degradable system, the bioactive agent is released when the matrix is ​​degraded in vivo. The bioactive agent may also be released by a combination of the two mechanisms. In some embodiments of the controlled-release matrices described herein, release of the bioactive agent is driven by a combination of both diffusion and degradation. The release rate can be controlled by varying the drug to polymer ratio (e.g., higher drug concentrations tend to result in faster release rates), by varying the chemical nature of the polymer matrix (e.g., inclusion of polymers with Tg below about 40°C or below about 0°C tends to result in faster dissolution rates than polymers with Tg above 40°C, and polymers that absorb water tend to elute drug more quickly than more hydrophobic polymers that do not absorb water). These variables can be controlled by the selection of materials used in the manufacturing process.

[0141] In some embodiments, the controlled-release matrix is ​​configured to release the bioactive agent. In some embodiments, the controlled-release matrix is ​​configured to release at least about 40% to up to about 60%, or at least 50%, of the bioactive agent within 12 hours of administration. In some embodiments, the controlled-release matrix is ​​configured to release at least about 40% to up to about 60%, or at least 50% of the bioactive agent within 24 hours of administration. In other embodiments, the controlled-release matrix is ​​configured to release at least about 80% to up to about 100%, or at least 90%, of the bioactive agent within 7 days of administration.

[0142] 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 acid) 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 approximately 60°C and is degraded by hydrolysis of its ester bonds under physiological conditions.

[0143] 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 of about 173°C to about 178°C.

[0144] Polyglycolide (PGA) is a biodegradable thermoplastic polyester prepared from glycolic acid by polycondensation or ring-opening polymerization. PGA has a melting point of about 225°C to about 230°C.

[0145] Poly(lactic-co-glycolic acid) polymer (PLGA) refers to a biodegradable copolymer of lactic acid and glycolic acid formed by random ring-opening copolymerization of glycolic acid and lactic acid monomers. During polymerization, the monomer units are linked to each other by ester bonds, producing an aliphatic polyester. PLGA is amorphous and has a glass transition temperature of approximately 40°C to 60°C. Generally, PLGA copolymers have a weight-average molecular weight of approximately 1000 Da to approximately 50,000 Da, or approximately 5000 Da to 25,000 Da. The ratio of lactic acid to glycolic acid can vary. In general, increasing the amount of lactic acid results in a polymer that degrades more slowly. Increasing the amount of glycolic acid results in a polymer that degrades more rapidly. Furthermore, increasing the amount of glycolic acid tends to lower the glass transition temperature (Tg) and water penetration into the polymer, which can result in faster release of the compound. Generally, the ratio of lactic acid to glycolic acid is about 100:0 to about 25:75, or about 60:40 to 40:60, or about 50:50.

[0146] 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).

[0147] In some embodiments, the polymeric material or polymer is biostable. Examples of biostable polymers include, but are not limited to, polyurethane, silicone rubber, styrene isobutylene-styrene block copolymer, ether-ester block copolymer (e.g., 1500-40D (RTP Co.)), and vinyl materials, including, but not limited to, poly(ethylene-co-vinyl acetate) (PEVA).

[0148] In some embodiments, the controlled-release matrix comprises an elastomeric polymeric material comprising a copolymer having an elastomeric (or "soft") component and a non-elastomeric (or "hard") component. In another embodiment, the elastomeric polymeric material comprises a polymer blend having an elastomeric component and a non-elastomeric component.

[0149] 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 heat, hardened by cooling, and then softened by heat again. Generally, thermoplastic materials are not crosslinked. However, in other embodiments, the compliant polymer or polymeric material can be crosslinked.

[0150] The bioactive agent can be incorporated into the controlled-release matrix by any of a variety of techniques known to those skilled 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.

[0151] In a melt extrusion process, a mixture containing 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 of a desired cross-sectional shape. The extruded material is collected under controlled conditions (e.g., velocity, temperature, and humidity) to obtain a product of 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 achieve the desired physical dimensions. For example, if the final extruded form is a film, the collection rate of the film can be increased relative to the mass flow rate of the extrudate to decrease the film's thickness, and conversely, to increase the film's thickness. The extrudate exits the orifice in a molten state, allowing the extrudate to elongate to its final dimensions. The extrudate is subsequently cooled by exposure to ambient conditions, a cooled liquid or gas bath, or a temperature-controlled surface such as a cooled roller to solidify the extrudate. In one embodiment, the melt extrusion process is used to form films. In an alternative embodiment, the melt extrusion process is used to form pellets or beads that can then be formed into the desired film or color configuration. Some advantages of melt extrusion processes include the absence of organic solvents, high throughput, and continuous manufacturing. Generally, processing temperatures are sufficient to melt the polymeric material without adversely affecting the biological activity of the bioactive agent. Generally, processing temperatures are 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 decomposition temperatures of the polymeric material and the bioactive agent. Furthermore, melt processing offers the ability to operate continuously, control operating parameters, and scale up manufacturing.

[0152] In an alternative embodiment, an injection molding process is used. In the injection molding process, a mixture containing a polymeric material and a bioactive agent is fed into a container, where it is heated to a temperature sufficient to melt the polymeric material, and then forced into a mold cavity, where it cools and hardens to the configuration of the mold cavity. Conditions (e.g., temperature and pressure) vary depending on the material being molded. In one embodiment, an injection molding process is used to form a film or collar.

[0153] 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 to form a film, for example, by evaporation. In one embodiment, the solvent is removed under vacuum (e.g., from about 15 in. Hg to about 28 in. Hg, depending on the volatility of the solvent). In another embodiment, the solvent is removed at elevated temperatures (e.g., from about 30°C to about 80°C). In an alternative embodiment, the polymer solution is applied to a substrate by a spray coating process. In the spray coating process, the polymer solution is supplied at a controlled flow rate by a positive displacement pump to, for example, a spray nozzle and an ultrasonic spray nozzle. The spray nozzle and substrate are moved in relative motion with one another at a controlled speed to achieve the desired coating thickness. The spray nozzle is attached to a three-axis motion control system (x, y, z) that can control the speed and position of the spray head relative to the substrate. Furthermore, if the substrate is a rolled film, it is traversed under the spray head by a roll-to-roll unwinding and rewinding device. The coating width is controlled by moving the spray nozzle in a specified path across the width of the substrate. Additionally, the height (z) of the spray nozzle above the substrate can be increased to achieve a wider coating width.

[0154] The solvent can be one in which one or more components of the polymeric material form a true solution. The bioactive agent can 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 non-halogenated alkanes such as hexane, cyclohexane, methylene chloride, 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 due to their excellent dissolving power for various polymers and bioactive agents.

[0155] excipients In certain embodiments, the calcium alpha-ketoglutarate compositions described herein include excipients. In some embodiments, the compositions disclosed herein include excipients such as suspending agents (e.g., methylcellulose), wetting agents (e.g., lecithin, lysolecithin, and / or long-chain fatty alcohols), and colorants, preservatives, flavoring agents, etc.

[0156] The compositions disclosed herein can also be incorporated into foods, such as cream cheese, butter, salad dressing, or ice cream, to facilitate solubilization, administration, and / or compliance in certain patient populations.

[0157] Preparations for oral use can be obtained as solid excipients, and optionally the resulting mixture is pulverized, and if desired, after adding suitable auxiliaries, the granular mixture is processed to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers, sugars such as lactose, sucrose, mannitol, or sorbitol; flavoring agents, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP).If desired, disintegrants can be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate.Active compounds can also be formulated as sustained-release preparations.

[0158] Sugar-coated tablet core can be provided with suitable coating.For this purpose, concentrated sugar solution can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.Dyes or pigments can be added to tablet or sugar-coated tablet coating for identification or to identify the characteristics of different combinations of active compound dosage.

[0159] Orally usable preparations include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and plasticizers (e.g., glycerol or sorbitol). Push-fit capsules may contain the active ingredient mixed 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 soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All compositions for oral administration should be in a dosage suitable for administration.

[0160] For injection, the compositions disclosed herein can be formulated in aqueous solutions, preferably physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. Such compositions can also contain one or more excipients, such as preservatives, solubilizers, fillers, lubricants, stabilizers, albumin, etc. Formulation methods are known in the art, for example, Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, Pa. These compositions can also be formulated for transmucosal administration, buccal administration, inhalation administration, parenteral administration, transdermal administration, and rectal administration.

[0161] In addition to the disclosed formulation, composition can also be formulated as depot preparation.Such long-acting formulation can be administered by implantation or transdermal delivery (for example, subcutaneous or intramuscular), intramuscular injection or transdermal patch.Therefore, for example, composition can be formulated with suitable polymer or hydrophobic material (for example, as emulsion in acceptable oil) or ion exchange resin, or as sparingly soluble derivative, for example, as sparingly soluble salt.

[0162] In some embodiments, 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 dissolve formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsed release formulations, multiparticulate formulations (e.g., nanoparticle formulations), and immediate-release controlled-release combined formulations.

[0163] In some embodiments, the formulation includes a carrier or carrier material selected based on its 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, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholate, phosphatidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sodium sugar stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, and any combination thereof. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth 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, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0164] In some cases, the formulation further contains a pH adjuster or buffer, including 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-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0165] In some cases, the formulation contains one or more salts in the amount necessary to make the osmotic pressure of the composition acceptable.Such salts include those with sodium, potassium or ammonium cation and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anion.Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0166] In some cases, the formulation includes a binder used to hold the calcium alpha-ketoglutarate and inactive ingredients together into a cohesive mixture. Suitable binders include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603, hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylase, magnesium aluminum silicate, polysaccharide acids, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars such as sucrose (e.g., Dipac®), glucose, dextrose, , molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, natural or synthetic gums such as acacia, tragacanth, gum ghatti, isapol shell mucilage, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, wax, sodium alginate, and any combination thereof.

[0167] In some cases, the formulation further comprises a diluent, which is used to stabilize calcium alpha-ketoglutarate because it provides a more stable environment.Salts dissolved in buffer solutions (which also provide pH control or maintenance) are utilized as diluents in the art, including but not limited to phosphate buffered saline.In certain instances, the diluent increases the bulk of the composition to facilitate compression or create sufficient bulk for a homogeneous blend for capsule filling. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose, e.g., Avicel®; dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugars, e.g., Di-Pac® (Amstar); mannitol, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate stearate, sucrose-based diluents, powdered sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed grain solids, amylase; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and any combination thereof.

[0168] In some cases, the formulation contains a disintegrant or disintegrant to promote the breakup or disintegration of the substance. The term "disintegrate" includes both the dissolution and dispersion of the dosage form when it comes into contact with gastrointestinal fluid. Examples of disintegrants include starch, such as natural starch, for example, corn starch or potato starch, pregelatinized starch, for example, National 1551 or Amijel®, or sodium starch glycolate, for example, Promogel® or Explotab®, cellulose, for example, wood products, methyl crystalline cellulose, for example, Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples of suitable crosslinking agents include Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked celluloses such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, carob, karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactants, resins such as cation exchange resins, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in mixed starches, and any combination thereof.

[0169] In some cases, the formulation includes a filler, such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, 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.

[0170] Glidants 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 fumerate, hydrocarbons such as mineral oil, or hydrogenated vegetable oils, such as hydrogenated soybean oil (Sterotex®), 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, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, polyethylene glycol (e.g., PEG-4000), or methoxypolyethylene glycol, such as Carbowax™, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica, such as Syloid™, Cab-O-Sil®, starch, such as corn starch, silicone oil, surfactants, and any combination thereof.

[0171] Plasticizers include compounds that are used to soften microencapsulation materials or film coatings and reduce brittleness.Suitable plasticizers include, for example, polyethylene glycols, such as PEG300, PEG400, PEG600, PEG1450, PEG3350, and PEG800, stearic acid, propylene glycol, oleic acid, triethylcellulose, and triacetin.Plasticizers also function as dispersants or wetting agents.

[0172] 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, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide, and any combination thereof.

[0173] Stabilizers include compounds such as any antioxidant, buffer, acid, preservative, and any combination thereof.

[0174] Suspending agents include polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol (e.g., polyethylene glycol having 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, hydroxymethylcellulose acetate stearate, polysorbate- 80, hydroxyethylcellulose, sodium alginate, gums such as gum tragacanth and gum acacia, guar gum, xanthans such as xanthan gum, sugars, cellulosics such as sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and any combination thereof.

[0175] Surfactants include compounds such as sodium lauryl sulfate, docusate sodium, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, such as Pluronic® (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 alkylphenyl ethers, such as Octoxynol 10 and Octoxynol 40. Sometimes surfactants are included to enhance physical stability or for other purposes.

[0176] Viscosity enhancing agents include, for example, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, and combinations thereof.

[0177] Wetting agents include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, docusate sodium, sodium oleate, sodium lauryl sulfate, docusate sodium, triacetin, Tween 80, vitamin E TPGS, ammonium salts, and any combination thereof.

[0178] Antifoaming agents are chemical additives that reduce and prevent foam formation in the preparation of oral liquid formulations. The terms antifoaming agent and defoamer are often used interchangeably. Commonly used agents are insoluble oils, polydimethylsiloxanes (e.g., simethicone) and other silicones, certain alcohols, stearates, and glycols. Additives are used to prevent foam formation or are added to break up already formed foam. Antifoaming agents reduce foaming during the preparation of oral liquid formulations, which can lead to coagulation of aqueous dispersions. In some embodiments, the calcium alpha-ketoglutarate compositions described herein include an antifoaming agent. In some embodiments, the antifoaming agent is simethicone.

[0179] In some embodiments, there is significant overlap among the excipients used in the calcium alpha-ketoglutarate compositions, formulations, and dosage forms described herein. Thus, the above excipients should be construed as merely exemplary, and not limiting, of the types of excipients that may be included in solid dosage forms of the compositions described herein.

[0180] Bilayer formulation In some embodiments, the compositions described herein are formulated as a bilayer formulation.In some cases, the bilayer formulation comprising calcium alpha-ketoglutarate has enhanced bioavailability and requires a smaller dosage.In some embodiments, the bilayer formulation is an oral dosage form that comprises an immediate release top layer and a controlled release core.

[0181] Controlled-release coated formulations In some embodiments, at least one controlled-release coating surrounds the core of the oral dosage form. In certain embodiments, the controlled-release coating is a stable, controlled-release monolithic coating formed by a process including coating the core with a coating composition to form a core coated with an intermediate coating, and curing the coated core to form a stable controlled-release coating. In at least one embodiment, the coating composition comprises an aqueous dispersion of a neutral ester copolymer that does not contain any functional groups, a polyglycol having a melting point of at least 55°C, and one or more secondary excipients. The curing is carried out at a temperature equal to or greater than the melting point of the polyglycol. In at least one embodiment, the stable controlled-release coating comprises a neutral ester copolymer that does not contain any functional groups, a polyglycol having a melting point of at least 55°C, and one or more secondary excipients.

[0182] The coating composition comprises an aqueous dispersion of a neutral ester copolymer that does not contain any functional groups. The aqueous dispersion of the neutral ester copolymer that does not contain any functional groups can be an ethyl acrylate and methyl methacrylate copolymer dispersion. Non-limiting examples of ethyl acrylate and methyl methacrylate copolymer dispersions include a 30% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate (e.g., Eudragit® NE30D), a 40% aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate (e.g., Eudragit® NE40D), Eudragit® NM30D, Kollicoat® EMM30D, and any combination thereof. In at least one embodiment, the neutral ester copolymer that does not contain any functional groups used in the controlled-release coating composition is Eudragit® NE30D, Eudragit® NE40D, or a mixture thereof. The neutral ester copolymer without any functional groups may be present in an amount of about 1% to about 35% by weight of the coating composition, in certain embodiments, depending on the therapeutically active agent used and the desired controlled release profile. In certain embodiments, the neutral ester copolymer without any functional groups is present in an amount of about 20% to about 99.5% by dry weight of the coat. In other embodiments, the neutral ester copolymer without any functional groups is present in an amount of about 25% to about 60% by dry weight of the coat. In still other embodiments, the neutral ester copolymer without any functional groups is present in an amount of about 37% to about 50% by dry weight of the coat. In some embodiments, the neutral ester copolymer without 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 dry weight of the coat. In certain embodiments, the neutral ester copolymer without any functional groups is present in the coating composition in an amount of about 0.4% to about 39.8% of the dry weight of the tablet, and in other embodiments, in an amount of about 0.8% to about 24% of the dry weight of the tablet.In some particular embodiments, the neutral ester copolymer not comprising any functional groups is present in the coating composition in an amount of about 2% to about 5.5% of the dry weight of the tablet, e.g., 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%, or about 5.4% of the dry weight of the tablet.

[0183] In some embodiments, the controlled-release dosage form does not swell in a dimensionally unrestricted manner upon absorption of water. In certain embodiments, there is some swelling of the controlled-release dosage form in a dimensionally restricted manner upon absorption of water. In certain embodiments, the controlled-release coating limits the swelling of the dosage form upon absorption of water.

[0184] The coating composition also includes a polyglycol having a melting point of at least about 55°C. The polyglycol having a melting point of at least about 55°C can be a polyethylene glycol having an average molecular weight ranging from about 4,000 daltons to about 35,000 daltons. Non-limiting examples of polyglycols 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 polyglycol 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 polyglycol used in the coating composition is polyethylene glycol 8000. The polyglycol can be present in an amount of about 0.1% to about 10% by weight of the coating composition in certain embodiments. In certain embodiments, the polyglycol is present in an amount of about 0.5% to about 28% by dry weight of the coat, while in other embodiments, the polyglycol is present in an amount of about 4% to about 17% by dry weight of the coat.In yet other embodiments, the polyglycol is present in an amount of about 7.2% to about 15.2% by dry weight of the coat, 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% by dry weight of the coat. ,approximately 8.8%,approximately 8.9%,approximately 9%,approximately 9.1%,approximately 9.2%,approximately 9.3%,approximately 9.4%,approximately 9.5%,approximately 9.6%,approximately 9.7%,approximately 9.8%,approximately 9.9%,approximately 10%,approximately 10.1%,approximately 10.2%,approximately 10.3%,approximately 10.4%,approximately 10.5%,approximately 10.6%,approximately 10.7%,approximately 10.8%,approximately 10.9%,approximately 11%, Approximately 11.1%, approximately 11.2%, approximately 11.3%, approximately 11.4%, approximately 11.5%, approximately 11.6%, approximately 11.7%, approximately 11.8%, approximately 11.9%, approximately 12%, approximately 12.1%, approximately 12.2%, approximately 12.3%, approximately 12.4%, approximately 12.5%, approximately 12.6%, approximately 12.7%, approximately 12.8%, approximately 12.9%, approximately 13%, approximately 13.1%, approximately The polyglycol is present in an amount of 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%. In certain embodiments, the polyglycol is present in the coating composition in an amount of about 0.1% to about 11.2% of the dry weight of the tablet. In other embodiments, the polyglycol is present in the coating composition in an amount of about 0.1% to about 8% of the dry weight of the tablet. In still other embodiments, the polyglycol is present in the coating composition in an amount of about 0.2% to about 2.8% of the dry weight of the tablet, e.g., 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% of the dry weight of the tablet.Other suitable polyglycol 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.

[0185] In addition to the copolymer and polyglycol, the coating composition may contain one or more other excipients. The excipients may include, but are not limited to, anti-adherents, emulsifiers, anti-foaming agents, hydrophilic agents, flavorings, coloring agents, sweeteners, and the like, and any combination thereof. In some embodiments, the excipients may affect the properties of the coating in a variety of ways, and many substances used in the coating formulations may therefore 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.

[0186] A hydrophilic agent may be included in the coating to promote wetting of the coating upon contact with gastrointestinal fluids. Such hydrophilic agents include hydrophilic water-soluble polymers such as hydroxypropyl methylcellulose (HPMC) (e.g., Pharmacoat® 606 or hypromellose), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, polyvinylpyrrolidone (Povidone® or Kollidon®), polyvinyl alcohol, polyethylene oxide, vinylpyrrolidone-vinyl acetate copolymer (Kollidon® VA64), polyethylene glycol-polyvinyl alcohol copolymer (Kollicoat® IR), copolymers thereof, 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., Aquacoat® CPD); cellulose acetate trimellitate, poly(methacrylic acid, ethyl acrylate) 1:1 (e.g., Eudragit® L30D-55); Kollicoat® MAE 30 D; poly(methacrylic acid, ethyl acrylate) 1:1 (e.g., Eudragit® L100-55); Kollicoat® MAE 30DP; Eudragit® FS 30D; hypromellose acetate succinate LF, MF, HF grades (e.g., AQOAT®), polyvinyl acetate phthalate, and mixtures thereof. When a hydrophilic agent is included in the coating composition, the agent may be present in certain embodiments in an amount of about 0.1% to about 10% by weight of the coating composition. In other embodiments, the hydrophilic agent is present in an amount of from about 0.1% to about 5% by weight of the coating composition, and in yet 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 of from greater than about 0% to about 35% by dry weight of the coat. In other embodiments, the hydrophilic agent is present in an amount of from about 8% to about 30% by dry weight of the coat.In still other embodiments, the hydrophilic agent is present in an amount of about 12% to about 26% by dry weight of the coat, such as 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 coat. In certain embodiments, the hydrophilic agent is present in an amount of about 0% to about 14% of the dry weight of the tablet, in other embodiments, in an amount of about 0.2% to about 6% of the dry weight of the tablet; and in still other embodiments, in an amount of about 0.8% to about 2.5% of the dry weight of the tablet; for example, 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% of the dry weight of the tablet.

[0187] The tackiness of the polymer film is important for the coating of dosage forms and the subsequent curing step (post-coating heat treatment). During the coating of either cellulosic or acrylic polymers, undesirable, sometimes irreversible, aggregation of some granules or beads, or in the worst case, the entire batch, can occur, especially at higher product processing temperatures. Therefore, the addition of an anti-blocking agent to the coating formulation is desirable. Anti-blocking agents that can be used include, but are not limited to, adipic acid, magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, sterotex, glyceryl 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-blocking agent. Talc also functions as a wetting agent. The mixture of anti-blocking agents can be manipulated. The amount of anti-blocking agent in certain embodiment coating compositions can range from about 1% to about 15% by weight of the coating dispersion, and in certain embodiments, from about 1% to about 7% by weight of the coating dispersion. In certain embodiments, the anti-blocking agent is present in an amount of greater than about 0% to about 50% by dry weight of the coat. In other embodiments, the anti-blocking agent is present in an amount of about 2% to about 40% by dry weight of the coat. In still other embodiments, the anti-blocking agent is present in an amount of about 10% to about 30% by dry weight of the coat, 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 dry weight of the coat.In certain embodiments, the anti-adherent agent is present in an amount of about 0% to about 20% of the dry weight of the tablet, in other embodiments in an amount of about 0% to about 12% of the dry weight of the tablet, and in still other embodiments in an amount of about 0.6% to about 7% of the dry weight of the tablet, e.g., 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%, or The coating composition is present in an amount of 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%.

[0188] Antifoaming agents that may be included in the coating composition include silicone oil, simethicone (e.g., simethicone emulsion), and mixtures thereof. In at least one embodiment, the antifoaming agent is simethicone. When present, the antifoaming agent may be present in an amount of about 0.5% or less by weight of the coating composition in certain embodiments, and in other specific embodiments, from about 0.1% to about 0.4% by weight of the coating composition. In certain embodiments, the antifoaming agent is present in an amount of greater than about 0% to about 3% by dry weight of the coat. In other embodiments, the antifoaming agent is present in an amount of about 0.4% to about 2% by dry weight of the coat. In still other embodiments, the antifoaming agent is present in an amount of about 0.8% to about 1.5% by dry weight of the coat, such as about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, and about 1.4% by dry weight of the coat. In certain embodiments, the antifoaming agent is present in an amount of about 0% to about 1.2% of the dry weight of the tablet, in other embodiments in an amount of about 0% to about 0.8% of the dry weight of the tablet; and in still other embodiments, in an amount of about 0% to about 0.2% of the dry weight of the tablet; 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% of the dry weight of the tablet.

[0189] The inclusion of an emulsifier (also called an emulsifier or emulgent) can be used to facilitate the actual emulsification during preparation of the coat and to provide emulsion stability during the product's shelf life. Useful emulsifiers for the coat 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 manipulable. In at least one embodiment, the emulsifier used is polysorbate 80 (polyoxyethylene sorbitan monooleate) (e.g., Tween® 80). The emulsifier(s), when present, may be present in an amount of greater than 0% to about 0.5% by weight of the coat composition in certain embodiments. In at least one embodiment, the emulsifier is present in an amount of about 0.1% to about 0.3% by weight of the coat composition. In certain embodiments, the emulsifier is present in an amount of greater than 0% to about 2% by weight of the dry weight of the coat. In other embodiments, the emulsifier is present in an amount of about 0.1% to about 1% by dry weight of the coat, and in still other embodiments, the emulsifier is present in an amount of about 0.25% to about 0.75% by dry weight of the coat, such as 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 dry weight of the coat. In certain embodiments, the emulsifier is present in an amount of greater than about 0% to about 0.8% of the dry weight of the tablet, in other embodiments, greater than about 0% to about 0.4% of the dry weight of the tablet; and in still other embodiments, greater than about 0% to about 0.2% of the dry weight of the tablet; 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% of the dry weight of the tablet.

[0190] Any colorants permitted in film coating formulations are always water-insoluble colors (pigments). Pigments have certain advantages over water-soluble colors in that they are chemically stable to light, provide better opacity and covering power, and tend to optimize the impermeability to water vapor of a particular film. Examples of suitable colorants include, but are not limited to, iron oxide pigments, titanium dioxide, and aluminum lakes. Mixtures are manipulable. In at least one embodiment, the pigment or colorant used is titanium dioxide. If present, the pigment or colorant may be present in an amount of about 0.1% to about 10% by weight of the coating composition in certain embodiments. In at least one embodiment, the colorant is present in an amount of 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 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 dry weight of the coating. In other embodiments, the colorant is present in an amount of greater than about 0% to about 10% by dry weight of the coat, and in still other embodiments, the colorant is present in an amount of greater than about 2.2% to about 6.2% by dry weight of the coat, such as 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%, or about 4.0% by dry weight of the coat. %, 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%. In certain embodiments, the colorant is present in the coating formulation in an amount of greater than about 0% to about 8% of the dry weight of the tablet, in other embodiments greater than about 0% to about 5% of the dry weight of the tablet, and in still other embodiments greater than about 0% to about 1% of the dry weight of the tablet, for example, 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% of the dry weight of the tablet.

[0191] In at least one embodiment, the second excipient in the controlled-release coating comprises at least one of a neutral ester copolymer not containing any functional groups (e.g., Eudragit® NE30D, Eudragit® NE40D, Eudragit® NM30D, Kollicoat® EMM30D, or mixtures thereof), HPMC (e.g., Pharmacoat® 606), talc (e.g., Talc 400), polyethylene glycol (e.g., 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 mixtures thereof), simethicone, polysorbate 80, titanium dioxide, and mixtures thereof.

[0192] In at least one embodiment, the stable controlled-release coating hydrates 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, upon oral administration to a patient, provides controlled release of an effective amount of the active drug to at least one region of the patient's upper gastrointestinal tract (e.g., the stomach).

[0193] 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 aqueous-based and not solvent-based (specific examples of dosage forms coated with aqueous-based controlled-release coatings are referred to as "AQ"). In some embodiments, the controlled-release coating is formed by a solvent-based process (e.g., "PharmaPASS™" compositions).

[0194] The coating composition can be applied to the cores containing an effective amount of a therapeutically active agent by a process that involves atomizing (spraying) the coating composition (solution or suspension) onto the tablet core bed. Some examples of equipment suitable for film coating include ACCELA COTA® (Manesty Machines, Liverpool, UK), HI-COATER® (Freund Company, Japan), DRIACOATER™ (Driam Metallprodukt GmbH, Germany), HTF / 150™ (GS, Italy), and IDA™ (Dumoulin, France). Examples of units that operate on the fluidized bed principle include AEROMATIC™ (Fielder, Switzerland and UK) and GLATT AG™ (Switzerland). In at least one embodiment, the equipment used is ACCELA COTA®.

[0195] The coating composition is delivered to the coating equipment from a peristaltic pump at the desired rate and sprayed onto the rotating or fluidizing tablet cores. The tablet cores are preheated to approximately 30°C. During the coating process, the product temperature range is maintained between about 25°C and about 35°C by adjusting the inlet and outlet air flow rates, inlet air temperature, and spray rate. Once a single layer of coating composition has been applied and spraying is complete, the coated tablet cores are dried at about 30°C to about 40°C for about 3 to about 5 minutes at low pan speed and low airflow. The pan is then readjusted to a jog speed, and drying is continued for about 12 to about 15 minutes.

[0196] The coated tablet cores are placed on a tray and cured in an electric or steam oven at a temperature above the melting point of the polyethylene glycol or its derivative (post-coating heat treatment). In at least one embodiment, the curing temperature is above the melting point of the polyethylene glycol or its derivative. In at least one embodiment, the curing time is from about 2 hours to about 7 hours. The cured-coated tablets are then cooled to about room temperature.

[0197] In certain other embodiments, the coated tablet cores are placed on a coating pan and cured in two stages. During the first stage, the coated tablet is cured at a first curing temperature (e.g., in certain embodiments, about 50°C to about 59°C) for a period of time (e.g., in certain embodiments, about 15 minutes to about 90 minutes; and in at least one embodiment, about 60 minutes). During the second stage, the coated tablet is cured at a second curing temperature at least equal to or higher than the melting point of the polyglycol (e.g., in certain embodiments, about 60°C to about 70°C) for an additional period of time (e.g., in certain embodiments, about 30 minutes to about 180 minutes; and in at least one embodiment, about 120 minutes). In at least one embodiment, the two-stage curing of the coated tablet reduces non-functional defects of the tablet caused by the curing process. In at least one embodiment, the two-stage curing process substantially eliminates non-functional defects of the tablet caused by the curing process. Non-functional defects in dosage forms caused by the curing process can include visual defects in the coating (e.g., reduced color uniformity and / or a dull appearance), defects in the surface of the coating (e.g., roughness of the coating surface and / or wrinkles in the coating), and adhesion of tablets to each other and / or to the coating pan. Additionally, reducing defects in tablet color and smoothness can improve tablet printing.

[0198] In some embodiments, coating formulations can be used to coat various calcium alpha-ketoglutarate cores and adjusted to achieve the desired drug release profile. The length and duration of the delay are controlled by the hydration rate and coat thickness. The drug release rate after the delay is determined by the thickness and permeability of the hydrated coat. Therefore, the hydration rate and permeability of the coat can be adjusted to achieve the desired controlled-release drug profile. There is no preferred coat thickness, as this depends on the drug used in the core and the desired controlled-release profile.

[0199] Other parameters to combine with the coat thickness include varying the concentration of some of the components of the stable coat composition and / or varying the curing temperature and length of time the coated tablet core is cured. One skilled in the art would know which parameter or combination of parameters to vary for the desired controlled release profile.

[0200] Immediate-release coated formulation In some embodiments, the immediate-release coating comprises calcium alpha-ketoglutaric acid and an additional agent as described herein. In some embodiments, an effective amount of an immediate-release active agent in immediate-release form is coated onto the formulation described herein. For example, if the extended release of calcium alpha-ketoglutaric acid from the formulation is due to a controlled-release coating, an immediate-release layer of an additional agent would be overcoated on top of the controlled-release coating. In some embodiments, the immediate-release layer of an additional agent is coated onto the surface of a substrate in which calcium alpha-ketoglutaric acid is incorporated into a controlled-release matrix. When multiple sustained-release substrates (e.g., multiparticulate systems such as pellets, spheres, beads, etc.) containing effective unit doses of calcium alpha-ketoglutaric acid are incorporated 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 as a powder or granules within the capsule. Alternatively, the gelatin capsule itself may be coated with an immediate-release layer of an additional agent.

[0201] A coating containing an immediate release of an additional agent, such as an antihistamine or antiemetic, can be applied 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) with water / isopropyl alcohol and triethyl acetate. Such an immediate-release coating can be spray-coated onto the tablet core. An immediate-release coating can also be applied using a press-coating process using a blend consisting of 80% by weight of promethazine and 20% by weight of lactose and hydroxypropylmethylcellulose type 2910.

[0202] 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 an immediate-release layer and / or the second layer is a controlled-release layer.

[0203] Formulation and route of administration The sustained-release compositions of calcium alpha-ketoglutarate disclosed herein can be formulated in a conventional manner using one or more physiologically acceptable carriers, such as excipients and auxiliaries, that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation will vary depending on the selected route of administration. Additional details regarding suitable excipients for the compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth 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, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0204] The calcium alpha-ketoglutarate compositions described herein are administered to a subject by multiple routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, inhalation, buccal, topical, rectal, or transdermal routes. In some embodiments, the calcium alpha-ketoglutarate-containing compositions described herein are formulated into any suitable dosage form, including, but not limited to, emulsions suitable for injection, nanosuspensions suitable for injection, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled-release formulations, fast-dissolve formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multiparticulate formulations, and immediate-release-controlled-release combination formulations.

[0205] In some embodiments, the calcium alpha-ketoglutarate is calcium alpha-ketoglutarate monohydrate. In some embodiments, the composition is an oral, buccal, nasal, or inhaled formulation. In some embodiments, the composition is in the form of a tablet or capsule.

[0206] In some embodiments, the composition for oral use is a tablet (such as a suspension tablet, fast-dissolving tablet, orally disintegrating tablet, rapid-disintegrating tablet, effervescent tablet, or caplet), pill, powder (such as a sterile-packed powder, dispensing powder, or effervescent powder), capsule (both soft and hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersion, solid solution, bioerodible dosage form, controlled-release formulation, pulsed-release dosage form, multiparticulate dosage form, pellet, granule, or aerosol. In some embodiments, the composition for oral use is a solid dosage form, e.g., a tablet, effervescent tablet, and capsule. In some embodiments, the solid dosage form is prepared by mixing particles of calcium alpha-ketoglutarate with one or more pharmaceutically acceptable excipients to form a bulk blend composition. When these bulk blend compositions are referred to as homogeneous, it means that the particles of calcium alpha-ketoglutarate are uniformly dispersed throughout the composition so that the composition can be subdivided into equally effective unit dosage forms (tablets, pills, capsules, etc.). The individual unit dosages may also include a film coating that disintegrates upon oral ingestion or contact with diluent.

[0207] For oral administration, the compositions disclosed herein can be readily formulated by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers allow the compositions disclosed herein to be formulated as tablets, e.g., chewable tablets, pills, dragees, capsules, troches, hard candies, liquids, gels, syrups, slurries, powders, suspensions, elixirs, wafers, and the like, for oral ingestion by the patient to be treated. Such formulations 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 present in an oral dosage form at concentration levels sufficient to provide the desired dosage unit, ranging from 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 weight of the composition.

[0208] Additional Agents In some embodiments, the sustained release calcium alpha-ketoglutarate composition 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.

[0209] In some embodiments, the composition comprises a vitamin. In some embodiments, the vitamin is vitamin A, vitamin B, vitamin C, or vitamin D.

[0210] In some embodiments, the vitamin is vitamin A. In some embodiments, the amount of vitamin A is between 500 IU and 5000 IU. In some embodiments, the amount of vitamin A is between 1000 IU and 3000 IU. In some embodiments, the amount of vitamin A is between 1000 IU and 2000 IU. In some embodiments, the amount of vitamin A is at least 500 IU. In some embodiments, the amount of vitamin A is up to 5,000 IU.In some embodiments, the amount of vitamin A ranges from 500 IU to 750 IU, 500 IU to 1,000 IU, 500 IU to 1,500 IU, 500 IU to 2,000 IU, 500 IU to 2,500 IU, 500 IU to 3,000 IU, 500 IU to 3,500 IU, 500 IU to 4,000 IU, 500 IU to 4,500 IU, 500 IU to 5,000 IU, 750 IU to 1,000 IU, 750 IU to 1,500 IU, 750 IU to 2,000 IU, 750 IU to 2,500 IU, 750 IU to 3,000 IU, 750 IU to 4,000 IU, 750 IU to 5,000 IU, 750 IU to 1,000 IU, 750 IU to 1,500 IU, 750 IU to 2,000 IU, 750 IU to 2,500 IU, 750 IU to 3,000 IU, 750 IU to 3,500 IU, 750 IU to 4,000 IU, 750 IU to 4,500 IU, 750 IU to 5,000 IU, 750 IU to 1,000 IU, 750 IU to 1,500 IU, 750 IU to 2,000 IU, 750 IU to 2,500 IU, 750 IU to 3,000 IU, 750 I 50IU~3,000IU, 750IU~3,500IU, 750IU~4,000IU, 750IU~4,500IU, 750IU~5,000IU, 1,000IU~1,500IU, 1,000IU~2,000IU, 1,000IU ~2,500IU, 1,000IU~3,000IU, 1,000IU~3,500IU, 1,000IU~4,000IU, 1,000IU~4,500IU, 1,000IU~5,000IU, 1,500IU~2,000IU, 1,50 0IU~2,500IU, 1,500IU~3,000IU, 1,500IU~3,500IU, 1,500IU~4,000IU, 1,500IU~4,500IU, 1,500IU~5,000IU, 2,000IU~2,500IU, 2,000IU~3,000IU, 2,000IU~3,500IU, 2,000IU~4,000IU, 2,000IU~4,500IU, 2,000IU~5,000IU, 2,500IU~3,000IU, 2,500IU~3,500 IU, 2,500 IU to 4,000 IU, 2,500 IU to 4,500 IU, 2,500 IU to 5,000 IU, 3,000 IU to 3,500 IU, 3,000 IU to 4,000 IU, 3,000 IU to 4,500 IU, 3,000 IU to 5,000 IU, 3,500 IU to 4,000 IU, 3,500 IU to 4,500 IU, 3,500 IU to 5,000 IU, 4,000 IU to 4,500 IU, 4,000 IU to 5,000 IU, or 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.

[0211] In some embodiments, the vitamin is vitamin D. In some embodiments, the amount of vitamin D is between 100 IU and 3000 IU. In some embodiments, the amount of vitamin D is between 200 IU and 2000 IU. In some embodiments, the amount of vitamin D is between 250 IU and 1000 IU. In some embodiments, the amount of vitamin D is between 100 IU and 3000 IU. In some embodiments, the amount of vitamin D is at least 100 IU. In some embodiments, the amount of vitamin D is up to 3,000 IU.In some embodiments, the amount of vitamin D is between 100 IU and 250 IU, between 100 IU and 500 IU, between 100 IU and 750 IU, between 100 IU and 1,000 IU, between 100 IU and 1,250 IU, between 100 IU and 1,500 IU, between 100 IU and 1,750 IU, between 100 IU and 2,000 IU, between 100 IU and 2,500 IU, between 100 IU and 3,000 IU, between 250 IU and 500 IU, between 250 IU and 750 IU, between 250 IU and 1,000 IU, between 250 IU and 1,250 IU , 250IU~1,500IU, 250IU~1,750IU, 250IU~2,000IU, 250IU~2,500IU, 250IU~3,000IU, 500IU~750IU, 500IU~1,000IU, 500IU~ 1,250IU, 500IU~1,500IU, 500IU~1,750IU, 500IU~2,000IU, 500IU~2,500IU, 500IU~3,000IU, 750IU~1,000IU, 750IU~1,250I U, 750IU~1,500IU, 750IU~1,750IU, 750IU~2,000IU, 750IU~2,500IU, 750IU~3,000IU, 1,000IU~1,250IU, 1,000IU~1,500IU , 1,000IU~1,750IU, 1,000IU~2,000IU, 1,000IU~2,500IU, 1,000IU~3,000IU, 1,250IU~1,500IU, 1,250IU~1,750IU, 1,250IU 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.

[0212] In some embodiments, the vitamin is nicotinamide riboside (NR). In some embodiments, the vitamin is nicotinamide mononucleotide (NMN).

[0213] In some embodiments, the composition comprises an antioxidant, hi some embodiments, the antioxidant is fisetin.

[0214] Example The following examples are provided for illustrative purposes only and are intended to be purely exemplary of the present disclosure and are not intended to limit the scope of the claims provided herein.

[0215] Example 1 General Manufacturing Procedure for Calcium Alpha-Ketoglutarate Extended-Release Tablets. Exemplary tablets contain 350-450 mg of alpha-ketoglutarate by weight based on the free acid. Additionally, exemplary tablets contain 450-650 mg of alpha-ketoglutarate by weight based on the salt and hydrate forms. Additionally, exemplary tablets contain 150-250 mg of calcium by weight when alpha-ketoglutarate is the calcium salt. Uncoated tablets have an average weight of about 1000-1000 mg, including about 1030 mg. Coated tablets have an average weight of about 1020-1120 mg, including about 1060 mg. Exemplary tablet cores include: [Table 1] [Table 2]

[0216] Exemplary coatings include: [Table 3]

[0217] calculation For example, calcium alpha-ketoglutarate monohydrate corresponds to: Alpha-ketoglutaric acid = 350 mg; Conversion factor = 1.26 (alpha-ketoglutaric anhydride); Converted amount = 441 mg; Standard LOD = 10%; standard assay = 98%; Standard calculation: (441x100x100) / (98x(100-10))=500mg; Also contains calcium element = 19.5-22%; Minimum value considered = 19.5%; 500 mg of CAKG contains 97.5 mg of elemental calcium.

[0218] Standard Manufacturing Procedures 1.Weighing Weigh all ingredients according to the amounts obtained in the recipe.

[0219] 2. Sifting 290.0 gm of HPMC K4 and 435.0 gm of HPMC K15 are blended in a double cone blender for 5 minutes and sieved through a 40# sieve. 686.0 gm of lactose monohydrate and 954.0 gm of microcrystalline cellulose are sieved through a 40# sieve. 2500.0 gm of calcium alpha-ketoglutarate monohydrate are then blended for 2 minutes and sieved through a 30# sieve. 50.0 gm of colloidal silicon dioxide are sieved through a 40# sieve and 50.0 gm of magnesium stearate are sieved through a 60# sieve. Each sieved material is collected individually in a plastic bag. (Temperature and RH should be NMT 27°C and 40% RH throughout the process.)

[0220] 3.Mixing and granulation The sieved ingredients (HPMCK4 and HPMCK15, calcium alpha-ketoglutarate monohydrate, lactose monohydrate, colloidal silicon dioxide, and microcrystalline cellulose) are blended in an 18 liter double cone blender at 16 rpm for 25 minutes. Magnesium stearate is added to the blend and blended in an 18 liter double cone blender for 5 minutes.

[0221] 4. Compression molding (Slugging) The dry mix material obtained in the previous step is compressed into tablets in a compression machine using suitable punch sizes to obtain tablets. Punch details: 19.6x8.4mm, capsule shape, standard concave, plain punch. Hardness: 2-5kg / cm 2 .

[0222] 5. Crushing The tablets are crushed using a 6.0 mm SS screen by screening through an 18# sieve to determine the final size of the granules. Note: (Compression and crushing is performed twice to obtain granules with suitable flow properties). Granule crushing parameters (target): 1) Bulk density - 0.6~0.7gm / ml; 2) Tap density - 0.9~1.0gm / ml; 3) Carr's index - 25 to 30%; and 4) Hausner ratio -1.3 to 1.4.

[0223] 6. Smooth Check sieve for damage before use. 98.75 gm of colloidal silicon dioxide is sieved through a 40# sieve. 86.25 gm of magnesium stearate is sieved through a 60# sieve. The crushed mass from step 5 is mixed with colloidal silicon dioxide in a double cone blender for 5 minutes. Magnesium stearate is added to the above blend in a double cone blender for 5 minutes. The lubricated granules are collected in a double polyethylene bag and tightly closed. In some embodiments, one or more of a flavoring agent, a vitamin, an antioxidant, and a sweetener are added to the composition during the lubrication step along with the magnesium stearate and / or colloidal silicon dioxide.

[0224] 7. Tablet compression Ambient parameters: 1) RH-NMT40%; 2) Temperature-NMT27℃; Pressure difference - NLT10Pascal; * Punch type: "D" tool; 19.6 x 8.4 mm, capsule-shaped, standard concave. Plain punch.

[0225] Turn the hand wheel and then operate the electrical controls to confirm a complete rotation of the turret. Feed the granules and set the machine according to the desired specifications. Confirm the tablets from one complete rotation.

[0226] 8.Film coating of tablets Add Instamoistshield white (ICMS2398) to the specified amount of isopropyl alcohol with stirring and disperse. Stir for an additional 5 minutes. Add methylene chloride to the specified amount from the above step and continue stirring for an additional 40-45 minutes to obtain a white, viscous, lump-free suspension. Pass the above suspension through a colloid mill with an "O" adjustable gap for 15 minutes. Filter the coating suspension through a 200-mesh nylon cloth. Turn on the exhaust and apply the film coating suspension to the tablets using a clean spray gun assembly (ensuring elegance). Continue stirring the coating suspension during tablet coaling. Thoroughly dry the film-coated tablets after achieving the appropriate weight gain (300%). Target average weight of film-coated tablets = 1060.0 mg. Once the target weight gain is achieved, dry the coated tablets in the coating pan for 30 minutes.

[0227] Example 2. Dissolution Profile of Calcium Alpha-Ketoglutarate Sustained Release [Solubility parameters] Vehicle: 900 mL of simulated gastric fluid (SGF) without enzymes Equipment: Paddle (with sinker) Speed: 75rpm Hours: 1st, 4th, 8th, and 12th hours [Chromatography conditions] Column: Inertsil ODS, 3V (250x4.6mm) 5µm or equivalent. Flow rate: 0.8mL / min Wavelength: 210nm Injection volume: 10μL Oven temperature: 30℃ Sample cooler temperature: 15℃ Elution mode: Isocratic

[0228] Enzyme-free simulated gastric fluid (SGF) (dissolution medium): 2.0 g of sodium chloride and 7.0 mL of concentrated hydrochloric acid are weighed and transferred into 1000 mL of water and mixed.

[0229] Buffer: Dissolve 2.72 gm of potassium dihydrogen orthophosphate in 1000 mL of water and add 2.0 mL of orthophosphoric acid.

[0230] Mobile phase: Prepare a mixture of 95 volumes of buffer and 5 volumes of acetonitrile, mix, filter, and degas before use.

[0231] Standard Solution: Accurately weigh 55 mg of calcium alpha-ketoglutarate standard solution and transfer to a 100 mL dry volumetric flask. Add 50 mL of dissolution medium. Dissolve and make up to volume with dissolution medium and mix.

[0232] Test Solution: With the dissolution parameters set, place one tablet into each container, taking care to eliminate any air bubbles from the surface of the tablet, and immediately start the apparatus. After 1, 4, 8, and 12 hours, withdraw 10 mL samples of the medium and replace the withdrawn volume with fresh liquid. Filter the withdrawn samples through a 0.45 micron nylon syringe filter. Discard the first few mL of filtrate. System suitability: Standard solutions are injected five times. The relative standard deviation of the replicate injections is less than 2%.

[0233] Procedure: 10 μL of each test solution is injected into the liquid chromatograph and the chromatogram is recorded. The response of the calcium alpha-ketoglutarate peak is measured. The drug release rate of calcium alpha-ketoglutarate is calculated from the calcium alpha-ketoglutarate peak area of ​​the standard to test the efficacy rate of the actual standard used. [Table 4]

[0234] Calculation: (AT / AS)x(W / 100)x(900 / LC)x(p / 100)x100 During the ceremony, AT—the peak area of ​​calcium alpha-ketoglutarate in the chromatogram obtained from each injection of the test solution; AS - Average peak area of ​​calcium alpha-ketoglutarate from chromatograms obtained by five replicate injections of standard solution; WS - weight of actual standard solution of calcium alpha-ketoglutarate (mg); LC - labeled amount; P - The potency of the actual standard solution of calcium alpha-ketoglutarate on such basis. Correction Factor: (amount collected at previous interval x % dissolution (% labeled amount)) / volume of dissolution medium 1-hour time point = % dissolution after 1 hour; 4th hour = 1-hour correction factor + Dissolution rate % after 4 hours. 8th hour = 1 hour correction factor + Correction factor for the fourth hour + Dissolution rate % after 8 hours. 12 hour time point = 1 hour correction factor + Correction factor for the fourth hour + 8th hour correction factor + Dissolution rate % after 12 hours. result: [Table 5] [Table 6]

[0235] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Again, numerous 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 in practicing the invention. The following claims define the scope of the disclosure, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0236] Method Example 1. Extending healthspan and / or lifespan in mice. Eighteen-month-old non-genetically modified mice are fed a control diet, optionally a control diet and an immediate-release formulation (positive control), or a control diet and a composition described herein (treatment group). The mice are not sacrificed but allowed to die naturally. The lifespan of the mice is compared between the treatment group and the control group, and optionally the positive control group. In addition to determining lifespan, the frailty of the mice is determined throughout the study by a non-invasive frailty index composed of 31 observations adapted from a clinically relevant frailty index. The compositions described herein extend lifespan, healthspan, and / or improve frailty compared to the control and positive control groups of both genders. Further details of the examples are described in Lucanic, M., Lithgow, GJ, & Alavez, S. (2013). Pharmacological lifespan extension of invertebrates. Ageing research reviews, 12(1), 445-458; Searle, SD, Mitnitski, A., Gahbauer, EA, Gill, TM, & Rockwood, K. (2008). A standard procedure for creating a frailty index. BMC geriatrics, 8(1), 24; and Whitehead (2014).

[0237] Method Example 2. Prolonging healthspan and / or lifespan in humans (male and female). The compositions described herein are administered orally or parenterally to male and female volunteers and compared to a placebo control group and, optionally, a positive control group receiving a commercially available Ca-AKG, such as immediate-release Ca-AKG. Volunteers are monitored for lifespan, healthspan, and frailty using one or more of 31 conventional frailty index observations. This is an open-label study comparing treatment and control groups, and optionally, a positive control group. Volunteers are evaluated at three time points: study entry (day 1), 3 months, and 6 months. At each visit, blood pressure, heart rate, weight, safety lab values, CRP, blood chemistry, hemoglobin A1C, and uric acid levels are obtained, and each participant completes a questionnaire.

[0238] Use blood chemistries to calculate participants' biological ages by one or more published algorithms, such as the method described in Belsky, DW, Caspi, A., Houts, R., Cohen, HJ, Corcoran, DL, Danese, A., & Sugden, K. (2015). Quantification of biological aging in young adults. Proceedings of the National Academy of Sciences, 112(30), E4104-E4110.

[0239] In one exemplary study design, volunteers are assigned to a control group, an optional positive control group, or a treatment group, with each volunteer taking two tablets daily for six months. The control group receives a placebo, the positive control group receives an immediate-release formulation, and the treatment group receives two tablets as follows: Men: A tablet containing 500 mg of calcium alpha-ketoglutarate monohydrate; 450 mcg of retinyl palmitate; and one or more release modifiers. Women: A tablet containing 500 mg of calcium alpha-ketoglutarate monohydrate; cholecalciferol 12.5 mcg (500 IU); and one or more multiple-release modifiers.

[0240] One or more primary outcomes will be assessed for each group. Primary outcomes will be determined by measuring the following vital signs and blood chemistries: [Table 7] TIFF2025124683000009.tif89160

[0241] References All publications, patents, and patent applications disclosed are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Claims

[Claim 1] A composition comprising: (a) a therapeutically effective amount of calcium alpha-ketoglutarate; and (b) a controlled-release matrix.

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