Sustained-release composition of alpha-ketoglutarate

Abstract

In a given embodiment, a sustained-release composition of alpha-ketoglutarate is described in this specification.

Description

Background Technology

[0001] Alpha-ketoglutarate is an important biological molecule that serves as a key intermediate of the Krebs cycle, a nitrogen transporter, and an auxiliary substance for molecular oxidation. Alpha-ketoglutarate anions play a crucial role in the metabolism of primarily 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. This known delivery method releases Ca-AKG within a short timeframe, resulting in spikes in blood concentration, faster excretion, and an increased frequency of Ca-AKG administration. Therefore, there is a need to discover alternative methods for the delivery of Ca-AKG.

[0002] It was unexpectedly discovered that when alpha-ketoglutarate is initially released in the stomach or upper gastrointestinal (GI) tract, the overall bioavailability of alpha-ketoglutarate is variable and / or low, resulting in less predictable administration guidelines and less predictable clinical outcomes. Controlled-release, sustained-release, and / or delayed-release formulations of Ca-AKG have been discovered. This specification describes 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,

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

[0004] (b) Controlled-release substrate

[0005] Compositions comprising [the following] are described herein. For example, the composition is characterized, may provide, or is provided to provide a release rate of 90% or less of the calcium alpha-ketoglutarate of one or more calcium alpha-ketoglutarate compositions in which the active ingredient is otherwise released in an uncontrolled manner over or during a predetermined time period, or is formulated without any controlled-release substrate. For comparison, exemplary examples of calcium alpha-ketoglutarate compositions formulated without any controlled-release substrate include, but are not limited to, Simplesa™ and Klaire Labs™.

[0006] In another embodiment, the present specification also discloses 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.

[0007] In another embodiment, the present specification also

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

[0009] One or more release control agents

[0010] A composition is disclosed that includes; and optionally further includes one or more of isomalt, vegetable wax (carnauba and / or rice bran), stearic acid, magnesium stearate, and silica.

[0011] In another embodiment, the present specification also

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

[0013] 450 mcg of retinyl palmitate;

[0014] One or more release control agents

[0015] A composition is disclosed that includes; and optionally further includes one or more of isomalt, vegetable wax (carnauba and / or rice bran), stearic acid, magnesium stearate, and silica.

[0016] In another embodiment, the present specification also

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

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

[0019] One or more release control agents

[0020] A composition is disclosed that includes; and optionally further includes one or more of isomalt, vegetable wax (carnauba and / or rice bran), stearic acid, magnesium stearate, and silica.

[0021] It should be understood that in the formulations described herein, such release-controlling 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.

[0022] It has been surprisingly discovered that, compared to alternative formulations in which the active ingredient is otherwise released in an uncontrolled manner or formulated without any controlled-release substrate, the formulations described herein may contain lower doses of the active ingredient, including lower doses of AKG and / or salts thereof. Without being bound by theory, the formulations described herein are believed to provide higher bioavailability and thus allow lower doses to be administered to achieve similar results. Specific details for implementing the invention

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

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

[0025] In a composition comprising a unit dose or dosage form of the preceding provision, the controlled-release substrate comprises hydroxypropylmethylcellulose (HPMC).

[0026] A composition comprising a unit dose or dosage form of any one of the preceding provisions, wherein hydroxypropylmethylcellulose (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, and about 220,000 to 300,000, and combinations thereof.

[0027] A composition comprising a unit dose or dosage form of any one of the preceding provisions, wherein the controlled-release substrate comprises HPMC having a number average molecular weight of about 68,000 to 95,000.

[0028] A composition comprising a unit dose or dosage form of any one of the preceding provisions, wherein the controlled-release substrate comprises HPMC having a number average molecular weight of about 115,000 to 150,000.

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

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

[0031] A composition comprising a unit dose or dosage form of any one of the preceding provisions, 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.

[0032] A composition comprising a unit dose or dosage form of any one of the preceding provisions, 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.

[0033] A composition comprising a unit dose or dosage form of any one of the preceding provisions, 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.

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

[0035] A composition comprising a unit dose or dosage form of any one of the preceding provisions, 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.

[0036] A composition comprising a unit dose or dosage form of any one of the preceding provisions, 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% of the total weight of the composition.

[0037] A composition comprising a unit dose or dosage form of any one of the preceding provisions, 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.

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

[0039] A composition comprising a unit dose or dosage form of any one of the preceding provisions, 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.

[0040] A composition comprising a unit dose or dosage form of any one of the preceding provisions, further comprising a sweetener; wherein the sweetener is isomalt.

[0041] A composition comprising a unit dose or dosage form of any one of the preceding provisions, further comprising a wax, wherein the wax is carnauba wax and / or rice bran wax.

[0042] A composition comprising a unit dose or dosage form of any one of the preceding provisions, further comprising one or more agents selected from the group consisting of surfactants, preservatives, flavoring agents, vitamins, antioxidants, and sweeteners.

[0043] A composition comprising a unit dose or dosage form of any one of the preceding provisions, 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).

[0044] A composition comprising a unit dose or dosage form of any one of the preceding provisions, further comprising an antioxidant; wherein the antioxidant is fisetin.

[0045] A composition comprising a unit dose or dosage form of any one of the preceding provisions, wherein the composition has a release rate of calcium alpha-ketoglutarate of a calcium alpha-ketoglutarate composition formulated without an uncontrolled or controlled-release substrate of about 90% or less; a release rate of calcium alpha-ketoglutarate of a calcium alpha-ketoglutarate composition formulated without an uncontrolled or controlled-release substrate of about 70% or less; a release rate of calcium alpha-ketoglutarate of a calcium alpha-ketoglutarate composition formulated without an uncontrolled or controlled-release substrate of about 60% or less; a release rate of calcium alpha-ketoglutarate of a calcium alpha-ketoglutarate composition formulated without an uncontrolled or controlled-release substrate of about 50% or less; a release rate of calcium alpha-ketoglutarate of a calcium alpha-ketoglutarate composition formulated without an uncontrolled or controlled-release substrate of about 40% or less; It is characterized by a release rate of calcium alpha-ketoglutarate of about 45% or less of the release rate of calcium alpha-ketoglutarate in a calcium alpha-ketoglutarate composition formulated without an uncontrolled or controlled-release substrate; and about 30% or less of the release rate of calcium alpha-ketoglutarate in a calcium alpha-ketoglutarate composition formulated without an uncontrolled or controlled-release substrate.

[0046] A composition comprising a unit dose or dosage form of any one of the preceding provisions, wherein the composition is characterized by a release rate of calcium alpha-ketoglutarate of about 30% or less after a time of about 0.5 to about 2 hours as measured by a paddle device while rotating a basket at 75 rpm, and the dissolution medium is 900 ml of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; and a composition characterized by a release rate of calcium alpha-ketoglutarate of about 25% or less after a time of about 0.5 to about 1.5 hours as measured by a paddle device while rotating a basket at 75 rpm, and the dissolution medium is 900 ml of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; Characterized by a release rate of calcium alpha-ketoglutarate of about 25% or less in the dissolution medium after about 1 hour, as measured by a paddle device while rotating the basket at 75 rpm, wherein the dissolution medium is 900 ml of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; characterized by a release rate of calcium alpha-ketoglutarate of about 20% or less in the dissolution medium after about 1 hour, as measured by a paddle device while rotating the basket at 75 rpm, wherein the dissolution medium is 900 ml of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; Characterized by a release rate of calcium alpha-ketoglutarate of about 60% or less in the dissolution medium after a time of about 4 to about 8 hours as measured by a paddle device while rotating the basket at 75 rpm, wherein the dissolution medium is 900 ml of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; characterized by a release rate of calcium alpha-ketoglutarate of about 60% or less in the dissolution medium after a time of about 8 hours as measured by a paddle device while rotating the basket at 75 rpm, wherein the dissolution medium is 900 ml of about 0.03 M NaCl and about 0.0.8M HCl; characterized by a release rate of calcium alpha-ketoglutarate of about 60% or less in the dissolution medium after about 4 to about 6 hours as measured by a paddle device while rotating the basket at 75 rpm, and the dissolution medium is about 0.03M NaCl and about 0.08M HCl at about 37°C, 900 ml; or characterized by a release rate of calcium alpha-ketoglutarate of about 60% or less in the dissolution medium after about 6 hours as measured by a paddle device while rotating the basket at 75 rpm, and the dissolution medium is about 0.03M NaCl and about 0.08M HCl at about 37°C, 900 ml.

[0047] A composition comprising a unit dose or dosage form of any one of the preceding provisions, wherein the composition is characterized by a release rate of calcium alpha-ketoglutarate of at least about 75% after a time of about 10 to about 11 hours as measured by a paddle device while rotating a basket at 75 rpm, and the dissolution medium is 900 ml of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; and a release rate of calcium alpha-ketoglutarate of at least about 75% after a time of about 10 hours as measured by a paddle device while rotating a basket at 75 rpm, and the dissolution medium is 900 ml of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; Characterized by a release rate of calcium alpha-ketoglutarate of more than approximately 75% in the dissolution medium after a time of about 9 to about 11 hours as measured by a paddle device while rotating the basket at 75 rpm, wherein the dissolution medium is 900 ml of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; characterized by a release rate of calcium alpha-ketoglutarate of more than approximately 75% in the dissolution medium after a time of about 9 hours as measured by a paddle device while rotating the basket at 75 rpm, wherein the dissolution medium is 900 ml of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; Characterized by a release rate of calcium alpha-ketoglutarate of more than 90% in the dissolution medium after a time of about 12 to about 15 hours as measured by a paddle device while rotating the basket at 75 rpm, wherein the dissolution medium is 900 ml of about 0.03 M NaCl and about 0.08 M HCl at about 37°C; characterized by a release rate of calcium alpha-ketoglutarate of more than 90% in the dissolution medium after a time of about 12 to about 14 hours as measured by a paddle device while rotating the basket at 75 rpm, wherein the dissolution medium is 900 ml of about 0.03 M NaCl and about 0.0.8M HCl; characterized by a release rate of calcium alpha-ketoglutarate of more than 90% after about 13 hours as measured by a paddle device while rotating the basket at 75 rpm, the dissolution medium is 900 ml of about 0.03M NaCl and about 0.08M HCl at about 37°C; or characterized by a release rate of calcium alpha-ketoglutarate of more than 90% after about 12 hours as measured by a paddle device while rotating the basket at 75 rpm, the dissolution medium is 900 ml of about 0.03M NaCl and about 0.08M HCl at about 37°C.

[0048] As a composition comprising a unit dose or dosage form of any one of the preceding provisions, calcium alpha-ketoglutarate is calcium alpha-ketoglutarate monohydrate.

[0049] A composition comprising a unit dose or dosage form of any one of the preceding provisions, comprising 525 mg of calcium alpha-ketoglutarate monohydrate.

[0050] A composition comprising a unit dose or dosage form of any one of the preceding provisions, wherein the dosage unit is configured for oral administration; the dosage unit is a tablet; and the dosage unit is a capsule.

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

[0052] Any unit capacity of any of the preceding provisions further includes the coating described in this specification.

[0053] The pharmacological treatment and prevention of the natural decline of age and age-related diseases have presented challenges to the medical community, partly due to the stringent characteristics required for pharmacological agents intended for these purposes. The aging patient population places an abnormally high burden on pharmacological therapies due to bioavailability, non-toxicity, and the absence of long-term side effects. Prevention requires the treatment of patients who may be at risk of age-related disorders but require agents that do not harm existing health because they are asymptomatic or mild. Treatment of patients with pre-existing age-related diseases demands high requirements for non-toxicity to avoid exacerbating existing health conditions. Furthermore, since the treatment or prevention of age-related disorders generally requires treatment with pharmacological agents over several years, these agents lack cumulative toxicity or long-term adverse effects on organ systems.

[0054] Recent findings suggest that aging is driven by molecular programs operating in animals, rather than simply by the accumulation of molecular damage. Studies in humans and model organisms to elucidate the molecular mechanisms of aging have demonstrated the existence of widely conserved longevity pathways. Various studies have demonstrated that dietary restriction, fasting, or calorie restriction can increase lifespan and delay the onset of numerous age-related phenotypes in various organisms, including the entire major model system described herein.

[0055] The mTOR signaling pathway has emerged as a pivotal aging-promoting pathway that is inhibited, particularly in yeast, nematodes, and fruit flies, due to the longevity-promoting effects of dietary restriction. In response to nutrient depletion, mTOR activity decreases, leading to altered regulation of mTOR substrates through phosphorylation, as well as downstream events that have been shown to promote lifespan and enhance tolerance to environmental stressors through the activation of changes in gene transcription and protein translation. Furthermore, dietary restriction is known to affect aging processes such as the AMPK pathway (activation), sirtuin pathway (elevation of protein levels), mitochondrial bioenergetics (activation), and IGF-1 pathway (inhibition), in addition to mTOR.

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

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. Methods and materials similar or equivalent to those described herein may be used in the practice or instruction of the invention, but suitable methods and materials are described below. In the event of a conflict, this specification shall prevail, including definitions. Furthermore, materials, methods, and examples are merely illustrative and are not intended to be limiting.

[0058] As used herein, the use of 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 “one,” “one,” and “this” include the plural referents unless the context otherwise clearly indicates. In this application, the use of “or” means “and / or” unless otherwise stated. Furthermore, the use of the term “comprising” as well as other forms, such as “comprising,” “comprising,” and “comprising,” is not limited.

[0059] "Alpha-ketoglutarate," "α-ketoglutarate," or "AKG" includes derivatives of alpha-ketoglutarate (e.g., derivatives presented in the literature [MacKenzie, et al. (2007) Mol Cell Biol 27(9):3282-3289]), analogs of alpha-ketoglutarate (e.g., phosphonate analogs cited in the literature [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, e.g., human alpha-ketoglutarate, porcine alpha-ketoglutarate, murine alpha-ketoglutarate, bovine alpha-ketoglutarate, etc.

[0060] As used herein, the terms “individual(s),” “object(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. No term requires or is limited to a situation characterized by supervision (e.g., continuous or intermittent) by a medical professional (e.g., physician, licensed nurse, practicing nurse, physician’s assistant, general or hospice staff).

[0061] As used herein, ranges and amounts may be expressed as "about" specific values ​​or ranges. "About" also includes exact amounts. Thus, "about 5 µl" means "about 5 µl" and "5 µl". Generally, the term "about" includes an amount expected to be within the experimental margin of error.

[0062] The terms “controlled-release dosing form” and “controlled-release layer” are used interchangeably and are defined as being selected to achieve therapeutic or convenience purposes where drug release characteristics over time and / or at location are not provided by a conventional immediate-release dosing form. The release rate of the active drug from the controlled-release layer or dosing form is controlled by the characteristics of the dosing form and / or in combination with physiological or environmental conditions rather than by physiological or environmental conditions alone. The controlled-release dosing form is used to maintain drug plasma levels within the therapeutic range. A controlled-release dosing form of a given embodiment attempts to deliver a therapeutically effective amount of active drug as a once-daily dose so that the Cmax / Cmin ratio in plasma at steady state is below the therapeutic index and to maintain the drug level at a constant effective level to provide therapeutic benefit over a given time period (e.g., a 24-hour period). In a given embodiment, the controlled-release dosing form provides a substantially constant or gradually decreasing drug release rate to provide plasma levels that remain substantially constant over time. In a given embodiment, the controlled-release administration form is designed to provide a rapid increase in the plasma concentration of the drug that is maintained substantially constant within the therapeutic range of the drug for a given period of time (e.g., a 24-hour period). Alternatively, in some other embodiments, the controlled-release administration form is designed to provide a rapid increase in the plasma concentration of the drug that is not maintained constant but decreases at a rate that maintains the plasma concentration within the therapeutic range for a given period of time (e.g., a 24-hour period).

[0063] The term “controlled-release substrate” refers to a substrate, such as a polymer substrate, capable of delivering a bioactive agent at a controlled rate over a set period of time. Although there may be an initial burst phase, the overall release kinetics of the bioactive agent from the substrate are generally linear, so that a relatively constant supply of the bioactive agent is released over a desired time period. The time period may vary from a few hours to several days depending on the bioactive agent and the intended use. Generally, it is desirable for the percentage of the bioactive agent released from the controlled substrate over the treatment period to be relatively high (e.g., at least about 50%, at least about 75%, at least about 90%, or at least about 95%) to avoid waste of unreleased bioactive agent. As used herein, the term “release controller” generally refers to a component that forms at least a portion of the controlled-release substrate, either individually or together.

[0064] The term “immediate-release” layer or dosage form refers substantially to the release of the active agent immediately upon administration. For example, immediate-release involves, but is not limited to, contact with gastric fluid and results in substantially complete dissolution within about one hour. The immediate-release component may also be referred to as instant release. The term “immediate-release” refers to the portion of the dosage form disclosed herein that delivers the active agent over a time period of less than one hour when used in relation to the dissolution profile discussed herein.

[0065] The terms “coating composition,” “coat composition,” “coating solution,” “coat solution,” “coating suspension,” and “coat suspension” as used herein are used interchangeably and are defined as a mixture of excipients used to produce a controlled-release coating. The coating composition is applied onto a calcium alpha-ketoglutarate core to form an intermediate coating, and the intermediate coating is cured to form a controlled-release coating.

[0066] The terms “effective dose,” “pharmaceutical effective dose,” or “therapeutic effective dose” refer to an amount of formulation that is non-toxic but sufficient to provide a desired biological, therapeutic, and / or prophylactic result. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or other desired alteration of the biological system. For example, an “effective dose” for therapeutic use is the amount of calcium alpha-ketoglutarate itself as disclosed herein, or a composition containing calcium alpha-ketoglutarate as disclosed herein, required to provide a clinically significant reduction of a disease or condition. In any individual case, an appropriate effective dose may be determined by a person skilled in the art using routine experimentation.

[0067] The term “pharmaceuticalally acceptable” as used herein refers to a material that is relatively non-toxic, such as a carrier or diluent, without eliminating the biological activity or properties of the compound; that is, the material is administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any component of the composition containing it.

[0068] The term “pharmaceuticalally acceptable salt” refers to a cationic form of a therapeutic agent combined with a suitable anion, or, in alternative embodiments, a form of a therapeutic agent consisting of an anionic form of a therapeutic agent combined with a suitable cation. [Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCR 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002]. Pharmaceutical salts are typically more soluble and dissolve more rapidly in gastric and intestinal fluids than nonionic species, and are therefore useful in solid dosage forms. Furthermore, since solubility is often a function of pH, selective dissolution is possible in one part of the digestive tract or another, and this function can be manipulated as an aspect of delayed and sustained-release behavior. Additionally, because salt-forming molecules can equilibrate with their neutral forms, passage across biological membranes can be regulated.

[0069] As used herein, “treatment” or “treating” refers to an approach to obtain a beneficial or desired result in relation to a disease, disorder, or medical condition, including but not limited to therapeutic benefits and / or preventive benefits. Therapeutic benefits mean the eradication or improvement of the underlying disorder being treated. Additionally, therapeutic benefits are achieved by the eradication or improvement of one or more physiological symptoms associated with the underlying disorder such that improvement is observed in the subject, even though the subject may still be suffering from the underlying disorder. In certain embodiments, for preventive benefits, the composition is administered to a subject at risk of developing a specific disease, or to a subject reporting one or more physiological symptoms of the disease, even if the diagnosis of the disease has not yet been made.

[0070] "Therapeutic effect," as used herein, includes therapeutic and / or preventive benefits as described above. Preventive effect includes delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0071] "Pharmaceuticalally acceptable carriers, diluents, or excipients" include, without limitation, any adjuvants, carriers, excipients, lubricants, sweeteners, diluents, preservatives, dyes, colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0072] Alpha-ketoglutarate (AKG)

[0073] The present specification describes a sustained-release composition of alpha-ketoglutarate.

[0074] In certain aspects, the present disclosure provides a composition comprising a compound (e.g., alpha-ketoglutarate salt) that is available for human consumption without FDA approval or is recognized as generally safe (GRAS). Such compounds may also be classified for the following reasons: a) because they are present in the FDA SCOGS database and are generally recognized as safe by the U.S. Food and Drug Administration; or b) because they are derived from plants present in a traditional diet (e.g., fruits, vegetables, herbs) and are therefore recognized by the scientific community as safe for consumption. In some embodiments, GRAS compounds are compounds available for human consumption without FDA approval.

[0075] In some embodiments, the compositions disclosed herein comprise AKG. Alpha-ketoglutarate or α-ketoglutarate (Formula 1) is also known as 2-oxopentanic acid, 2-ketoglutaric acid, 2-oxoglutaric acid, and oxoglutaric acid. At physiological pH, α-ketoglutarate exists in one or more deprotonated forms as depicted by Formula 2. α-ketoglutarate is an intermediate in the Krebs cycle of eukaryotes and is biosynthesized in these organisms from isocitrate (in the course of the Krebs cycle) or L-glutamate (via alanine transaminases). Both α-ketoglutarate and its corresponding salts are commercially available through preparation from fermentation cultures (see, for example, U.S. Patent No. 2,776,926) or chemical synthesis from closely related compounds.

[0076]

[0077] α-ketoglutarate is an important regulator of bioenergy in cells, consistent with its role in energy production through the Krebs cycle, and is involved as an inhibitor of the ATP synthase subunit β and an indirect inhibitor of the kinase mTOR, resulting from the partial inhibition of the mitochondrial electron transport chain.

[0078] In some embodiments, α-ketoglutarate is provided as a free acid (α-ketoglutaric acid). In some embodiments, α-ketoglutarate is provided as a mono salt or a bis salt. In other embodiments, α-ketoglutarate is provided as a monosodium salt, a disodium salt, a monopotassium salt, or a dipotassium salt. In yet another additional embodiment, α-ketoglutarate is [listed in the US FDA Orange Book] Orange Book It is provided as a monovalent or divalent salt together with other cations listed in ). These cations include calcium, diolamine, lithium, lysine, magnesium, meglumine, olamine, tromethamine, and zinc. In further embodiments, the salt of α-ketoglutarate is provided as an anhydrous salt, a hemihydrate, a monohydrate, or a dihydrate.

[0079] Additionally, in certain aspects, the present specification discloses compositions comprising an α-ketoglutarate salt. In some embodiments, the α-ketoglutarate is provided as a calcium salt (Ca-AKG). In some embodiments, the calcium α-ketoglutarate may be hydrated calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate may be monohydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate may be hemihydrate calcium α-ketoglutarate. In some embodiments, the calcium α-ketoglutarate may be anhydrous calcium α-ketoglutarate.

[0080] In some embodiments, the composition disclosed herein comprises an ester of α-ketoglutarate. In some embodiments, the ester of α-ketoglutarate is a methyl ester of α-ketoglutarate. In some embodiments, the ester of α-ketoglutarate is a dimethyl ester of α-ketoglutarate. In some embodiments, the ester of α-ketoglutarate is an ethyl ester of α-ketoglutarate. In some embodiments, the ester of α-ketoglutarate is a diethyl ester of α-ketoglutarate.

[0081] 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 another embodiment, alpha-ketoglutarate is provided as a monovalent or divalent salt with other cations listed in the U.S. FDA Orange Book. These cations include calcium, diolamine, lithium, lysine, magnesium, meglumine, olamine, tromethamine, and zinc.

[0082] Sustained-release composition of alpha-ketoglutarate

[0083] In one aspect, the present specification describes a composition comprising a therapeutically effective amount of calcium alpha-ketoglutarate and a controlled-release substrate; wherein the composition is characterized, may provide, or is configured to provide a release rate of calcium alpha-ketoglutarate of 90% or less of the release rate of calcium alpha-ketoglutarate of one or more calcium alpha-ketoglutarates formulated without any controlled-release substrate over a predetermined time period or during that period.

[0084] In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 80% or less of the release rate of calcium alpha-ketoglutarate formulated without any control-release substrate. In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 70% or less of the release rate of calcium alpha-ketoglutarate formulated without any control-release substrate. In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 60% or less of the release rate of calcium alpha-ketoglutarate formulated without any control-release substrate. In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 50% or less of the release rate of calcium alpha-ketoglutarate formulated without any control-release substrate. In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 40% or less of the release rate of calcium alpha-ketoglutarate of a calcium alpha-ketoglutarate formulated without any control-release substrate. In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 30% or less of the release rate of calcium alpha-ketoglutarate of a calcium alpha-ketoglutarate formulated without any control-release substrate. In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 20% or less of the release rate of calcium alpha-ketoglutarate of a calcium alpha-ketoglutarate formulated without any control-release substrate. In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 10% or less of the release rate of calcium alpha-ketoglutarate of a calcium alpha-ketoglutarate formulated without any control-release substrate.In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 5% or less of the release rate of calcium alpha-ketoglutarate of calcium alpha-ketoglutarate formulated without any control-release substrate.

[0085] Amount of calcium alpha-ketoglutarate

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

[0087] 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 another embodiment, 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, approx. 43% w / w, approx. 44% w / w, approx. 45% w / w, approx. 46% w / w, approx. 47% w / w, approx. 48% w / w, approx. 49% w / w, approx. 50% w / w, approx. 51% w / w, approx. 52% w / w, approx. 53% w / w, approx. 54% w / w, approx. 55% w / w, approx. 56% w / w, approx. 57% w / w, approx. 58% w / w, approx. 59% w / w, approx. 60% w / w, approx. 61% w / w, approx. 62% w / w, approx. 63% w / w, approx. 64% w / w, approx. 65% w / w, approx. 66% w / w, approx. 67% w / w, approx. 68% w / w, approx. 69% It is equivalent to 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.

[0088] 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.

[0089] Controlled-release substrate

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

[0091] In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of 18,000 to 44,000. In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of at least 18,000. In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of up to 44,000.In some embodiments, the control-emission substrate is 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 27,000, 20,000 to 30,000, 20,000 to 33,000, 20,000 to 36,000, 20,000 to 39,000, 20,000 to 41,000, 20,000 to 44,000, 23,000 to 27,000, 23,000 to 30,000, 23,000 to 33,000, 23,000 to 36,000, 23,000 to 39,000, 23,000 to 41,000, 23,000 to 44,000, 27,000 to 30,000, 27,000 to 33,000, 27,000 to 36,000, 27,000 to 39,000, 27,000 to 41,000, 27,000 to 44,000, 30,000 to 33,000, 30,000 to 36,000, 30,000 to 39,000, 30,000 to 41,000, 30,000 to 44,000, 33,000 to 36,000, 33,000 to 39,000, 33,000 to 41,000, 33,000 to 44,000, 36,000 to 39,000, 36,000 to 41,000, 36,000 to 44,000, 39,000 to 41,000, 39,000 to 44,000, or 41,000 to It comprises HPMC having a number average molecular weight of 44,000. In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of 18,000, 20,000, 23,000, 27,000, 30,000, 33,000, 36,000, 39,000, 41,000, or 44,000.

[0092] In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of 65,000 to 102,000. In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of at least 65,000. In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of up to 102,000. In some embodiments, the control-emission substrate is 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, 68,000 to 87,000, 68,000 to 91,000, 68,000 to 95,000, 68,000 to 99,000, 68,000 to 102,000, 71,000 to 74,000, 71,000 to 77,000, 71,000 to 80,000, 71,000 to 83,000, 71,000 to 87,000, 71,000 to 91,000, 71,000 to 95,000, 71,000 to 99,000, 71,000 to 102,000, 74,000 to 77,000, 74,000 to 80,000, 74,000 to 83,000, 74,000 to 87,000, 74,000 to 91,000, 74,000 to 95,000, 74,000 to 99,000, 74,000 to 102,000, 77,000 to 80,000, 77,000 to 83,000, 77,000 to 87,000, 77,000 to 91,000, 77,000 to 95,000, 77,000 to 99,000, 77,000 to 102,000, 80,000 to 83,000, 80,000 to 87,000, 80,000 to 91,000, 80,000 to 95,000, 80,000 to 99,000, 80,000 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, It includes HPMC having a number average molecular weight of 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 control-release substrate 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.

[0093] In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of 103,000 to 156,000. In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of at least 103,000. In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of up to 156,000. In some embodiments, the control-emission substrate is 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 to 115,000, 109,000 to 118,000, 109,000 to 123,000, 109,000 to 128,000, 109,000 to 133,000, 109,000 to 138,000, 109,000 to 142,000, 109,000 to 146,000, 109,000 to 150,000, 109,000 to 156,000, 115,000 to 118,000, 115,000 to 123,000, 115,000 to 128,000, 115,000 to 133,000, 115,000 to 138,000, 115,000 to 142,000, 115,000 to 146,000, 115,000 to 150,000, 115,000 to 156,000, 118,000 to 123,000, 118,000 to 128,000, 118,000 to 133,000, 118,000 to 138,000, 118,000 to 142,000, 118,000 to 146,000, 118,000 to 150,000, 118,000 to 156,000, 123,000 to 128,000, 123,000 to 133,000,123,000 to 138,000, 123,000 to 142,000, 123,000 to 146,000, 123,000 to 150,000, 123,000 to 156,000, 128,000 to 133,000, 128,000 to 138,000, 128,000 to 142,000, 128,000 to 146,000, 128,000 to 150,000, 128,000 to 156,000, 133,000 to 138,000, 133,000 to 142,000, 133,000 to It includes HPMC having a number average molecular weight of 146,000, 133,000 to 150,000, 133,000 to 156,000, 138,000 to 142,000, 138,000 to 146,000, 138,000 to 150,000, 138,000 to 156,000, 142,000 to 146,000, 142,000 to 150,000, 142,000 to 156,000, 146,000 to 150,000, 146,000 to 156,000, or 150,000 to 156,000. In some embodiments, the control-release substrate 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.

[0094] In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of 170,000 to 320,000. In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of at least 170,000. In some embodiments, the control-release substrate comprises HPMC having a number average molecular weight of up to 320,000. In some embodiments, the control-emission substrate is 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 to 190,000, 180,000 to 200,000, 180,000 to 210,000, 180,000 to 220,000, 180,000 to 230,000, 180,000 to 240,000, 180,000 to 260,000, 180,000 to 280,000, 180,000 to 300,000, 180,000 to 320,000, 190,000 to 200,000, 190,000 to 210,000, 190,000 to 220,000, 190,000 to 230,000, 190,000 to 240,000, 190,000 to 260,000, 190,000 to 280,000, 190,000 to 300,000, 190,000 to 320,000, 200,000 to 210,000, 200,000 to 220,000, 200,000 to 230,000, 200,000 to 240,000, 200,000 to 260,000, 200,000 to 280,000, 200,000 to 300,000, 200,000 to 320,000, 210,000 to 220,000, 210,000 to 230,000,210,000 to 240,000, 210,000 to 260,000, 210,000 to 280,000, 210,000 to 300,000, 210,000 to 320,000, 220,000 to 230,000, 220,000 to 240,000, 220,000 to 260,000, 220,000 to 280,000, 220,000 to 300,000, 220,000 to 320,000, 230,000 to 240,000, 230,000 to 260,000, 230,000 to It includes HPMC having a number average molecular weight of 280,000, 230,000 to 300,000, 230,000 to 320,000, 240,000 to 260,000, 240,000 to 280,000, 240,000 to 300,000, 240,000 to 320,000, 260,000 to 280,000, 260,000 to 300,000, 260,000 to 320,000, 280,000 to 300,000, 280,000 to 320,000, or 300,000 to 320,000. In some embodiments, the control-release substrate 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.

[0095] emission rate

[0096] In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 30% or less in a dissolving medium at a time of 0.5 to 2 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving 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 release rate of calcium alpha-ketoglutarate of 25% or less in a dissolving medium at a time of 0.5 to 2 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving 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 release rate of calcium alpha-ketoglutarate of 25% or less in a dissolving medium at a time of 0.5 to 1.5 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving 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 release rate of calcium alpha-ketoglutarate of 20% or less in a dissolving medium at a time of 0.5 to 1.5 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving 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 release rate of calcium alpha-ketoglutarate of 30% or less in one hour in a dissolving medium as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving 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 release rate of calcium alpha-ketoglutarate of 25% or less per hour in the dissolution medium as measured by a paddle device while the basket is rotated 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 release rate of calcium alpha-ketoglutarate of 20% or less per hour in the dissolution medium as measured by a paddle device while the basket is rotated 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 release rate of calcium alpha-ketoglutarate of 19% or less in one hour in a dissolving medium as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving 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 release rate of calcium alpha-ketoglutarate of 18% or less per hour in the dissolution medium as measured by a paddle device while the basket is rotated 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 release rate of calcium alpha-ketoglutarate of 17% or less in one hour in a dissolving medium as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving 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 release rate of calcium alpha-ketoglutarate of 16% or less in one hour in a dissolving medium as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving 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 release rate of calcium alpha-ketoglutarate of 15% or less per hour in the dissolution medium as measured by a paddle device while the basket is rotated 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 release rate of calcium alpha-ketoglutarate of 60% or less in a dissolving medium over a period of 4 to 8 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving 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 release rate of calcium alpha-ketoglutarate of 60% or less in a dissolving medium over a period of 4 to 6 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving 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 release rate of calcium alpha-ketoglutarate of 60% or less in the dissolution medium at 8 hours as measured by a paddle device while the basket is rotated 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 release rate of calcium alpha-ketoglutarate of 60% or less in 7 hours in a dissolving medium as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving 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 release rate of calcium alpha-ketoglutarate of 60% or less in the dissolution medium at 6 hours as measured by a paddle device while the basket is rotated 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 release rate of calcium alpha-ketoglutarate of 60% or less in 5 hours in a dissolving medium as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving 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 release rate of calcium alpha-ketoglutarate of 55% or less in the dissolution medium at 5 hours as measured by a paddle device while the basket is rotated 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 release rate of calcium alpha-ketoglutarate of 50% or less in the dissolution medium at 5 hours as measured by a paddle device while the basket is rotated 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 provides a release rate of calcium alpha-ketoglutarate of 50% or less in 4 hours in a dissolving medium as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0117] In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 45% or less in the dissolution medium at 4 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolution medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0118] In some embodiments, the composition provides a release rate of calcium alpha-ketoglutarate of 40% or less in the dissolution medium at 4 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolution medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0119] In some embodiments, the composition provides a release rate of at least 75% of calcium alpha-ketoglutarate in a dissolving medium over a period of 9 to 11 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0120] In some embodiments, the composition provides a release rate of more than 75% of calcium alpha-ketoglutarate in a dissolving medium over a period of 9 to 10 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0121] In some embodiments, the composition provides a release rate of at least 75% of calcium alpha-ketoglutarate in a dissolving medium over a period of 10 to 11 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0122] In some embodiments, the composition provides a release rate of more than 75% of calcium alpha-ketoglutarate in a dissolving medium in 9 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0123] In some embodiments, the composition provides a release rate of more than 75% of calcium alpha-ketoglutarate in a dissolving medium over 10 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0124] In some embodiments, the composition provides a release rate of more than 75% of calcium alpha-ketoglutarate in a dissolving medium at 11 hours, measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0125] In some embodiments, the composition provides a release rate of 90% or less of calcium alpha-ketoglutarate in a dissolving medium over a period of 11 to 15 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0126] In some embodiments, the composition provides a release rate of more than 90% of calcium alpha-ketoglutarate in a dissolving medium over a period of 11 to 14 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0127] In some embodiments, the composition provides a release rate of more than 90% of calcium alpha-ketoglutarate in a dissolving medium over a period of 11 to 13 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0128] In some embodiments, the composition provides a release rate of more than 90% of calcium alpha-ketoglutarate in a dissolving medium over a period of 11 to 12 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0129] In some embodiments, the composition provides a release rate of more than 90% of calcium alpha-ketoglutarate in a dissolving medium over a period of 12 to 15 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0130] In some embodiments, the composition provides a release rate of more than 90% of calcium alpha-ketoglutarate in a dissolving medium over a period of 12 to 14 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0131] In some embodiments, the composition provides a release rate of more than 90% of calcium alpha-ketoglutarate in a dissolving medium over a period of 12 to 13 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0132] In some embodiments, the composition provides a release rate of more than 90% of calcium alpha-ketoglutarate in 11 hours in a dissolving medium as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0133] In some embodiments, the composition provides a release rate of more than 90% of calcium alpha-ketoglutarate in a dissolving medium in 12 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0134] In some embodiments, the composition provides a release rate of more than 90% of calcium alpha-ketoglutarate in a dissolving medium in 13 hours as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

[0135] In some embodiments, the composition provides a release rate of more than 90% of calcium alpha-ketoglutarate in a dissolving medium at 14 hours, measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at about 37°C.

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

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

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

[0139] In some embodiments, the composition comprises a first diluent. In some embodiments, the amount of the first diluent is 11% to 29% 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 up to 29% of the total weight of the composition. In some embodiments, the amount of the first diluent is 11% to 14%, 11% to 17%, 11% to 19%, 11% to 20%, 11% to 21%, 11% to 23%, 11% to 25%, 11% to 27%, 11% to 29%, 14% to 17%, 14% to 19%, 14% to 20%, 14% to 21%, 14% to 23%, 14% to 25%, 14% to 27%, 14% to 29%, 17% to 19%, 17% to 20%, 17% to 21%, 17% to 23%, 17% to 25%, 17% to 27%, 17% to 27%, with respect to the total weight of the composition. 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 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% with respect to the total weight of the composition.

[0140] 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 up to 29% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is 11% to 14%, 11% to 17%, 11% to 19%, 11% to 20%, 11% to 21%, 11% to 23%, 11% to 25%, 11% to 27%, 11% to 29%, 14% to 17%, 14% to 19%, 14% to 20%, 14% to 21%, 14% to 23%, 14% to 25%, 14% to 27%, 14% to 29%, 17% to 19%, 17% to 20%, 17% to 21%, 17% to 23%, 17% to 25%, 17% to 17%, 17% to 20%, 17% to 21%, 17% to 23%, 17% to 25%, 17% to 27%, 17% to 29%, 19% to 20%, 19% to 21%, 19% to 23%, 19% to 25%, 19% to 27%, 19% to 29%, 20% to 21%, 20% to 23%, 20% to 25%, 20% to 27%, 20% to 29%, 21% to 23%, 21% to 25%, 21% to 27%, 21% to 29%, 23% to 25%, 23% to 27%, 23% to 29%, 25% to 27%, 25% to 29%, or 27% to 29%. In some embodiments, the amount of microcrystalline cellulose is about 11% of the total weight of the composition.In some embodiments, the amount of microcrystalline cellulose is about 14% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 17% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 19% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 20% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 21% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 23% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 25% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 27% of the total weight of the composition. In some embodiments, the amount of microcrystalline cellulose is about 29% of the total weight of the composition.

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

[0142] 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% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is up to 19% of the total weight of the composition.In some embodiments, the amount of lactose monohydrate is 4% to 6%, 4% to 8%, 4% to 10%, 4% to 11%, 4% to 12%, 4% to 13%, 4% to 14%, 4% to 15%, 4% to 17%, 4% to 19%, 6% to 8%, 6% to 10%, 6% to 11%, 6% to 12%, 6% to 13%, 6% to 14%, 6% to 15%, 6% to 17%, 6% to 19%, 8% to 10%, 8% to 11%, 8% to 12%, 8% to 13%, 8% to 14%, 8% to 15%, 8% to 8% to 19%, with respect to the total weight of the composition. 17%, 8% to 19%, 10% to 11%, 10% to 12%, 10% to 13%, 10% to 14%, 10% to 15%, 10% to 17%, 10% to 19%, 11% to 12%, 11% to 13%, 11% to 14%, 11% to 15%, 11% to 17%, 11% to 19%, 12% to 13%, 12% to 14%, 12% to 15%, 12% to 17%, 12% to 19%, 13% to 14%, 13% to 15%, 13% to 17%, 13% to 15%, 13% to 17%, 13% to 19%, 14% to 15%, It is 14% to 17%, 14% to 19%, 15% to 17%, 15% to 19%, or 17% to 19%. In some embodiments, the amount of lactose monohydrate is about 4% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 6% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 8% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 10% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 11% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 12% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 13% of the total weight of the composition.In some embodiments, the amount of lactose monohydrate is about 14% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 15% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 17% of the total weight of the composition. In some embodiments, the amount of lactose monohydrate is about 19% of the total weight of the composition.

[0143] In some embodiments, the composition comprises 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% 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.

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

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

[0146] In some embodiments, the composition comprises 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 up to 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.

[0147] 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 amount of 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.

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

[0149] Composition of alpha-ketoglutarate

[0150] In another aspect, the present specification describes 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.

[0151] In some embodiments, the amount of calcium alpha-ketoglutarate is 50 mg to 5000 mg. In some embodiments, the amount of calcium alpha-ketoglutarate is 100 mg to 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.

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

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

[0154] In some embodiments, the vitamin is vitamin D. In some embodiments, the amount of vitamin D is 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, vitamin D is cholecalciferol.

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

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

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

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

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

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

[0161] Controlled-release substrate formulation

[0162] In certain embodiments, the composition of calcium alpha-ketoglutarate described herein comprises a controlled-release substrate. There are many mechanisms by which a bioactive agent can be released from a controlled-release substrate. Two mechanisms include diffusion and / or degradation. Diffusion occurs when the bioactive agent is released through pores within the polymer substrate or by passing between the polymer chains of the substrate. In a diffusion system, the bioactive agent may diffuse throughout the substrate or be localized within the substrate or within a reservoir adjacent to the substrate. In a reservoir system, a reservoir of the bioactive agent within the polymer substrate, for example, a solid drug, a diluted solution, or a high-concentration drug solution, is surrounded by a controlled-release material, through which the bioactive agent may diffuse. In a degradable system, the bioactive agent is released as the substrate degrades in vivo. The bioactive agent may also be released by a combination of the two mechanisms. In some embodiments of the controlled-release substrate described herein, the release of the bioactive agent is driven by a combination of both diffusion and degradation. The release rate can be controlled by changing the drug-to-polymer ratio (e.g., higher drug concentrations tend to result in a faster release rate) and by changing the chemistry of the polymeric substrate (e.g., the incorporation of a polymer with a Tg of less than about 40°C or less than about 0°C tends to result in a faster elution rate than a polymer with a Tg greater than 40°C, and water-absorbing polymers tend to elute the drug more rapidly than more hydrophobic polymers that do not absorb water). These variables may also be controlled by the selection of materials used in the manufacturing process.

[0163] In some embodiments, the control-release substrate is configured to release the bioactive agent as described above. In some embodiments, the control-release substrate is configured to release at least about 40%, up to about 60%, or at least 50% of the bioactive agent within 12 hours of administration. In some embodiments, the control-release substrate is configured to release at least about 40% and up to about 60%, or at least 50% of the bioactive agent within 24 hours of administration. In another embodiment, the control-release substrate is configured to release at least about 80% or up to about 100%, or at least 90% of the bioactive agent within 7 days of administration.

[0164] In some embodiments, the controlled-release substrate is biodegradable. In some embodiments, the controlled-release substrate comprises a biodegradable polyester. Examples of biodegradable polyesters include polycaprolactone (PCL), polylactic acid (PLA), polyglycolide (PGA), and copolymers thereof, such as poly(lactic acid-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 octanoate. Polycaprolactone has a melting point of about 60°C and degrades under physiological conditions by hydrolysis of its ester linkages.

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

[0166] Polyglycolide (PGA) is a biodegradable, thermoplastic polyester produced from glycolic acid by polycondensation or ring-opening polymerization. It has a melting point of about 225°C to about 230°C.

[0167] Poly(lactic acid-co-glycolic acid) polymer (PLGA) refers to a biodegradable copolymer of lactic acid and glycolic acid formed by the random ring-opening copolymerization of monomers of glycolic acid and lactic acid. During polymerization, monomer units are linked together by ester linkages, thereby yielding an aliphatic polyester. PLGA is amorphous and has a glass transition temperature of about 40°C to 60°C. Generally, PLGA copolymers have a weight-average molecular weight of about 1,000 Da to about 50,000 Da, or about 5,000 Da to 25,000 Da. The ratio of lactic acid to glycolic acid may vary. Generally, an increase in the amount of lactic acid results in a polymer that degrades more slowly. An increase in glycolic acid results in a polymer that degrades more rapidly. In addition, an increase in glycolic acid tends to decrease the glass transition temperature (Tg) and water penetration into the polymer, which can lead to a more rapid 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.

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

[0169] 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 from RTP Co.), and vinyl materials including, but not limited to, poly(ethylene-co-vinyl acetate) (PEVA).

[0170] In some embodiments, the control-release substrate comprises an elastomer polymer material comprising a copolymer of an elastomer (or "soft") component and a non-elastomer (or "hard") component. In another embodiment, the elastomer polymer material comprises a polymeric blend having an elastomer component and a non-elastomer component.

[0171] In some embodiments, the conforming polymer or polymeric material is thermoplastic. As used herein, the term “thermoplastic” refers to a polymer or polymeric material that can be softened by heating, hardened by cooling, and then softened again by repeated heating. Generally, thermoplastic materials are not cross-linked. However, in another embodiment, the conforming polymer or polymeric material may be cross-linked.

[0172] A bioactive agent may be incorporated into the control-release substrate using any of the various techniques known to those skilled in the art. In one embodiment, the bioactive agent is dispersed throughout the control-release substrate. Techniques for manufacturing the control-release substrate include, but are not limited to, melt extrusion, injection molding, or spray casting.

[0173] In a melt extrusion process, a mixture comprising a polymer material and a bioactive agent is combined in an extruder, heated to a temperature at which the polymer material melts, and then discharged through an orifice of the desired cross-sectional shape. The extruded material is collected under controlled conditions (e.g., speed, temperature, and humidity) to obtain a product of the desired dimensions. In one embodiment, the mass flow rate of the extruder 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 in proportion to the mass flow rate of the extruder to decrease the film thickness, or conversely, to increase the film thickness. The extruder is discharged through the orifice in a molten state to stretch the extruder to the final dimensions. The extruder is subsequently cooled by exposure to ambient conditions, a cooled liquid or gas bath, or by exposure to a temperature-controlled surface, such as a cooled roller, to solidify the extruder. In one embodiment, a film is formed using a melt extrusion process. In an alternative embodiment, a pellet or bead is formed using a melt extrusion process that can subsequently be molded into a desired film or color composition. Some of the advantages of the melt extrusion process include the absence of organic solvents, high-speed mass processing, and continuous manufacturing. Generally, the processing temperature is sufficient to melt the polymer material without adversely affecting the biological activity of the bioactivator. Typically, the processing temperature is at least about 80°C or about 100°C, less than about 180°C, less than 160°C, or about 110°C to about 150°C. In some embodiments, the specific temperature depends on the melting and decomposition temperatures of the polymer material and the bioactivator. Additionally, the melt process provides continuous operation capabilities, control of operating parameters, and manufacturing scale-up capabilities.

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

[0175] In another embodiment, solvent casting technology may be used. In a solvent casting process, a polymer material and a bioactive agent are combined with a suitable solvent to form a polymer solution, which is then cast onto a substrate. Subsequently, the solvent is removed to form a film, for example, by evaporation. In one embodiment, the solvent is removed under vacuum (e.g., about 15 Hg to about 28 Hg, depending on the volatility of the solvent). In another embodiment, the solvent is removed at an elevated temperature (e.g., about 30°C to about 80°C). In an alternative embodiment, the polymer solution is applied to the substrate by a spray coating process. In the spray coating process, the polymer solution is supplied to, for example, a spray nozzle and an ultrasonic spray nozzle at a speed controlled by a volumetric pump. The spray nozzle and the substrate are moved relative to each other at a controlled speed to achieve a desired coating thickness. The spray nozzle is mounted on a 3-axis motion control system (xyz) capable of controlling the speed and position of the spray head relative to the substrate. Additionally, if the substrate is a rolled film, the substrate is traversed below the spray head by a roll-to-roll unwinding and winding device. The coating width is controlled by moving the spray nozzle along a specific path across the width of the substrate. Furthermore, the height (z) of the spray nozzle above the substrate can be increased to achieve a wider coating width.

[0176] The solvent may be one in which one or more components of the polymer material form a true solution. The bioactive agent may be soluble in the solvent or form a dispersion throughout the solvent. Suitable solvents include, but are not limited to, alcohols (e.g., methanol, butanol, propanol, and isopropanol), alkanes (e.g., halogenated or non-halogenated alkanes, e.g., 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 solubility for various polymers and bioactive agents.

[0177] Brothers

[0178] In certain embodiments, the calcium alpha-ketoglutarate composition described herein includes excipients. In some embodiments, the composition disclosed herein includes excipients, such as suspending agents (e.g., methylcellulose), wetting agents (e.g., lecithin, lysolecithin and / or long-chain fatty alcohols), as well as coloring agents, preservatives, flavoring agents, etc.

[0179] The composition disclosed herein may also be incorporated into food, e.g., cream cheese, butter, salad dressing, or ice cream, to facilitate solubilization, administration, and / or compliance in a given patient population.

[0180] Formulations for oral use may be obtained as solid excipients, and optionally, the resulting mixture may be ground, and if desired, a suitable adjuvant added and the granulated mixture processed to obtain tablets and coated tablet cores. Suitable excipients are, in particular, sugars containing fillers, e.g., lactose, sucrose, mannitol, or sorbitol; flavor elements, cellulose preparations, e.g., corn starch, wheat starch, rice starch, potato starch, gelatin, tragercant gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If necessary, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or salts thereof, e.g., sodium alginate, may be added. The active compound may also be formulated as a sustained-release formulation.

[0181] A suitable coating may be provided on the core of the sugar-coated tablet. For this purpose, a concentrated sugar solution may be used and may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated tablet coating for identification or to characterize different combinations of active compound dosages.

[0182] Preparations suitable for oral use include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules may contain an 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 oil, liquid paraffin, or liquid polyethylene glycol. A stabilizer may also be added. All compositions for oral administration must be in a suitable dosage for administration.

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

[0184] In addition to the disclosed formulations, the composition may also be formulated as a depot formulation. Such long-acting formulations may be administered by implantation or transdermal delivery (e.g., subcutaneous or intramuscular), intramuscular injection, or the use of a transdermal patch. Thus, for example, the composition may be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0185] In some embodiments, the formulations of the compositions disclosed herein include aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate-release formulations, controlled-release formulations, rapid-dissolving formulations, tablets, capsules, pills, delayed-release formulations, extended-release formulations, pulsed-release formulations, multiparticulate formulations (e.g., nanoparticle formulations), and mixed immediate- and controlled-release formulations.

[0186] In some embodiments, the formulation comprises a carrier or carrier material selected based on compatibility with the composition disclosed herein and characteristics of the release profile 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 ester, sodium casein, soy lecithin, taurocholic acid, phosphotidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sodium stearoyl lactylate, carrageenan, monoglycerides, diglycerides, pregelatinized starch, and any combination thereof. For example, the literature [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 l999)]

[0187] In some cases, the formulation comprises a pH adjuster or buffer, comprising an acid such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; a base such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and a buffer such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. These acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

[0188] In some cases, the formulation comprises one or more salts in an amount necessary to make the osmotic concentration of the composition within an acceptable range. These salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0189] In some cases, the formulation includes a binder used to hold calcium alpha-ketoglutarate and inert components together in an agglomerate mixture. Suitable binders include carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g., Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose 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, polysaccharidic acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragercant, dextrin, sugars, e.g., sucrose (e.g., Dipac®), glucose, Includes, but is not limited to, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, natural or synthetic gums, e.g., acacia, tragacanth, ghatti gum, mucilage of psyllium husk, 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.

[0190] In some cases, the formulation further includes a diluent used to stabilize calcium alpha-ketoglutarate, as this provides a more stable environment. Salts dissolved in a buffer solution (which also provides pH adjustment or maintenance) are used as diluents in the art, including but not limited to phosphate-buffered salt solutions. In certain cases, the diluent increases the volume of the composition to create a sufficient volume for a homogeneous blend for capsule filling to facilitate pressing. These 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, pressable sugars, e.g., Di-Pac® (Amstar); Mannitol, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluent, confectionery sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrate; hydrolyzed grain solids, amylase; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and any combination thereof.

[0191] In some cases, the formulation includes a disintegrant or a disintegrant to promote the destruction or breakdown of the substance. The term "disintegrant" includes both a solubilizer and a dispersant in the dosage form when in contact with gastric fluid. Examples of disintegrants include starch, e.g., natural starch, e.g., corn starch or potato starch, pregelatinized starch, e.g., National 1551 or Amijel®, or sodium starch glycolate, e.g., Promogel® or Explotab®, cellulose, e.g., wood products, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® Pl 00, Emcocel®, Vivacel®, Ming Tia® and Solka-Floc®, methylcellulose, croscarmellose, or cross-linked cellulose, e.g., cross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer, crospovidone, It includes cross-linked polyvinylpyrrolidone, alginates, e.g., alginic acid or salts of alginic acid, e.g., sodium alkinate, clay, e.g., Veegum® HV (magnesium aluminum silicate), gums, e.g., agar, guar, locust bean, karaya, pectin or tragacanth, sodium starch glycolate, bentonite, natural sponge, surfactants, resins, e.g., cation-exchange resins, citrus pulp, sodium lauryl sulfate of blended starch, and any combination thereof.

[0192] In some cases, the formulation comprises a filler, such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrate, dextran, starch, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and any combination thereof.

[0193] Lubricants and lubricants are also optionally included in the formulations disclosed herein to prevent, reduce, or inhibit adhesion or friction of the materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, sodium stearyl fumarate, hydrocarbons, e.g., mineral oil, or halogenated vegetable oils, e.g., hydrogenated soybean oil (Sterotex®), higher fatty acids and their alkali metal and alkaline earth metal salts, e.g., 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, e.g., Carbowax™, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica, e.g., Syloid™, Cab-O-Sil®, starch, e.g., corn starch, silicone oil, surfactants, and their Includes any combination.

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

[0195] Solubilizing agents include compounds such as triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium docusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, 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.

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

[0197] The suspension is a compound, e.g., polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone / vinyl acetate copolymer (S630), polyethylene glycol (e.g., polyethylene glycol has 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, hydroxymethyl cellulose acetate stearate, polysorbate-80, hydroxyethyl cellulose, sodium alginate, gum, e.g., tragercanth gum and acacia gum, guar gum, e.g., xanthan gum, sugar, cellulose sugar, cellulose compound, e.g., sodium It includes carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethyl cellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, and any combination thereof.

[0198] Surfactants include compounds such as, for example, sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, poloxamer, bile salt, glycerol monostearate, copolymers of ethylene oxide and propylene oxide, for example, Pluronic® (BASF), and any combination thereof. Additional surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, for example, polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers, for example, octoxynol 10, octoxynol 40. Sometimes, surfactants are included to improve physical stability or for other purposes.

[0199] Viscosity enhancers include, for example, methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, hydroxypropylmethylcellulose phthalate, carbomer, polyvinyl alcohol, alginate, acacia, chitosan, and combinations thereof.

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

[0201] Antifoamers are chemical additives that reduce and inhibit foam formation during the preparation of oral liquid formulations. The terms antifoamer and defoamer are often used interchangeably. Commonly used formulations 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 down foam that has already formed. Antifoamers reduce foam during the preparation of oral liquid formulations, which may result in the coagulation of aqueous dispersions. In some embodiments, the calcium alpha-ketoglutarate compositions described herein contain an antifoamer. In some embodiments, the antifoamer is simethicone.

[0202] In some embodiments, there is significant overlap between the excipients used in the compositions, formulations, and dosage forms of calcium alpha-ketoglutarate described herein. Accordingly, the additives listed above should be considered merely as examples of the types of additives that may be included in the solid dosage forms of the compositions described herein, and are not limited thereto.

[0203] double-layer formulation

[0204] In some embodiments, the compositions described herein are formulated as bilayer formulations. In some cases, bilayer formulations containing calcium alpha-ketoglutarate have improved bioavailability and lower dosages. In some embodiments, the bilayer formulation is an oral administration form comprising an immediate-release top layer and a controlled-release core.

[0205] Control-release coating formulation

[0206] In some embodiments, at least one control-release coating surrounds a core in the form of an oral administration. In a given embodiment, the control-release coating is a stable control-release monolithic coating formed by a process comprising coating the core with a coating composition to form a coated core having an intermediate coating, and curing the coated core to form a stable control-release coating. In at least one embodiment, the coating composition comprises an aqueous dispersion of a neutral ester copolymer without any functional groups, a polyglycol having a melting point of 55°C or higher, and one or more second excipients. Curing is performed at a temperature at least above the melting point of the polyglycol. In at least one embodiment, the stable control-release coating comprises a neutral ester copolymer without any functional groups, a polyglycol having a melting point of at least 55°C, and one or more second excipients.

[0207] The coating composition comprises an aqueous dispersion of a neutral ester copolymer free of any functional groups. The aqueous dispersion of a neutral ester copolymer free of functional groups may 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 combinations thereof. In at least one embodiment, the neutral ester copolymer free of any functional groups used in the controlled-release coating composition is Eudragit® NE30D, Eudragit® NE40D, or a mixture thereof. A neutral ester copolymer without any functional groups may be present in a given embodiment in an amount of about 1% to about 35% by weight of the coating composition, depending on the therapeutic active agent used and the desired controlled-release profile. In a given embodiment, 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 another embodiment, 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 yet another embodiment, 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 group is present in amounts 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 some embodiments, the neutral ester copolymer without any functional group is about 0. by dry weight of the tablet.It is present in the coating composition in an amount of 4% to about 39.8%. In another embodiment, it is present in an amount of about 0.8% to about 24% by dry weight of the tablet. In some other embodiments, a neutral ester copolymer without any functional group is present in an amount of about 2% to about 5.5% by dry weight of the tablet, for example, 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% by dry weight of the tablet. It is present in the coating composition in amounts of about 5.1%, about 5.2%, about 5.3%, and about 5.4%.

[0208] In some embodiments, the controlled-release dosage form does not swell in a dimensionally unregulated manner upon water absorption. In certain embodiments, there is slight swelling of the controlled-release dosage form in a dimensionally regulated manner upon water absorption. In certain embodiments, the controlled-release coating regulates the swelling of the dosage form upon water absorption.

[0209] The coating composition also comprises a polyglycol having a melting point of at least about 55°C. The polyglycol having a melting point of at least about 55°C may be a polyethylene glycol having an average molecular weight in the range of about 4,000 daltons to about 35,000 daltons. Non-limiting examples of polyglycol 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 a given embodiment, 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. In a given embodiment, the polyglycol may be present in an amount of about 0.1% to about 10% by weight of the coating composition. In a given embodiment, the polyglycol is present in an amount of about 0.5% to about 28% by dry weight of the coat. In another embodiment, the polyglycol is present in an amount of about 4% to about 17% by dry weight of the coat. In another embodiment, the polyglycol is about 7.2% to about 15.2% by dry weight of the coat, for example, about 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9%, about 9.1%, about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9.8%, about 9.9%, about 10%, about 10.1%, about 10.2%, about 10.3%, about 10.4%, approx. 10.5%, approx. 10.6%, approx. 10.7%, approx. 10.8%, approx. 10.9%, approx. 11%, approx. 11.1%, approx. 11.2%, approx. 11.3%, approx. 11.4%, approx. 11.5%, approx. 11.6%, approx. 11.7%, approx. 11.8%, approx. 11.9%, approx. 12%, approx. 12.1%, approx. 12.2%, approx. 12.3%, approx. 12.4%, approx. 12.5%, approx. 12.6%, approx. 12.7%, approx. 12.8%, approx. 12.9%, approx. 13%, approx. 13.1%, approx. 13.2%, approx. 13.3%, approx. 13.4%, approx. 13.5%, It is present in amounts of 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 a given embodiment, 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 another embodiment, 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 another embodiment, polyglycol is present in the coating composition in amounts of about 0.2% to about 2.8% by dry weight of the tablet, for example, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, and about 2.7% by dry weight of the tablet.Other suitable polyglycol derivatives having a melting point of about 55°C or higher include, but are not limited to, Poloxamer 188, Poloxamer 338, Poloxamer 407, polyethylene oxide, polyoxyethylene alkyl ether, polyoxyethylene stearate, and mixtures thereof.

[0210] The coating composition comprises, in addition to the copolymer and polyglycol, one or more other excipients. Such excipients may include, but are not limited to, anti-stick agents, emulsifiers, defoaming agents, hydrophilic agents, flavoring agents, coloring agents, sweeteners, etc. In some embodiments, the excipients may affect the properties of the coat in a series of ways, and thus many materials used in the coat formulation may be described as multifunctional. A skilled worker, based on their technical knowledge, will know which excipients are suitable for the desired controlled-release coating composition.

[0211] Hydrophilic agents may be included in the coat to promote wetting of the coat when in contact with gastric fluids. Such hydrophilic agents include hydrophilic water-soluble polymers, e.g., hydroxypropyl methylcellulose (HPMC) (e.g., Pharmacoat® 606 or Hypromellose), hydroxypropyl cellulose (HPC), methyl cellulose, 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 a given embodiment, the hydrophilic formulation comprises a pH-dependent polymer, non-limiting examples thereof including 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 30 DP; Eudragit® FS 30D; hypromellose acetate succinate grades LF, MF, HF (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 an amount of about 0.1% to about 10% by weight of the coating composition in a given embodiment. In another embodiment, it may be present in an amount of about 0.1% to about 5% by weight of the coating composition, and in yet another embodiment, in an amount of about 0.1% to about 3% by weight of the coating composition.In a given embodiment, the hydrophilic agent is present in an amount greater than about 0% to about 35% of the dry weight of the coat. In another embodiment, the hydrophilic agent is present in an amount of about 8% to about 30% of the dry weight of the coat. In yet another embodiment, the hydrophilic agent is present in an amount of about 12% to about 26% of the dry weight of the coat, for example, 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% of the dry weight of the coat. In a given embodiment, the hydrophilic agent is present in an amount of about 0% to about 14% of the dry weight of the tablet; in another embodiment, in an amount of about 0.2% to about 6% of the dry weight of the tablet; And in another embodiment, in an amount of about 0.8% to about 2.5% by dry weight of the tablet; for example, in an amount of about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, and about 2.4% by dry weight of the tablet.

[0212] The tackiness of polymer films is important for coating in dosage form and subsequent curing steps (heat treatment after coating). During coating with cellulose or acrylic polymers, particularly at higher product processing temperatures, unwanted, and sometimes irreversible, aggregation of multiple granules or beads, or in the worst case, aggregation of the entire batch, may occur. Therefore, it is desirable to add an anti-tack agent to the coating formulation. Anti-tack agents that may be used include, but are not limited to, adipic acid, magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, sterotex, glycerol monostearate, talc (e.g., Talc 400), sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and mixtures thereof. In at least one embodiment, talc (e.g., Talc 400) is used as an anti-tack agent. Talc may also act as a wetting agent. Mixtures of anti-tack agents may be used. The amount of anti-adhesion agent in the coating composition of a predetermined embodiment may be in the range of about 1% to about 15% by weight of the coating dispersion, and in a predetermined embodiment, about 1% to about 7% by weight of the coating dispersion. In a predetermined embodiment, the anti-adhesion agent is present in an amount greater than about 0% to about 50% by dry weight of the coat. In another embodiment, the anti-adhesion agent is present in an amount of about 2% to about 40% by dry weight of the coat. In yet another embodiment, the anti-adhesion agent is present in an amount of about 10% to about 30% by dry weight of the coat; For example, it is present in amounts of 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% of the dry weight of the coat.In a given embodiment, the anti-stick agent is in an amount of about 0% to about 20% of the dry weight of the tablet; in another embodiment, in an amount of about 0% to about 12% of the dry weight of the tablet; and in yet another embodiment, in an amount of about 0.6% to about 7% of the dry weight of the tablet; For example, based on the dry weight of the tablet, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about It is present in the coating formulation in amounts of 4.2%, approximately 4.3%, approximately 4.4%, approximately 4.5%, approximately 4.6%, approximately 4.7%, approximately 4.8%, approximately 4.9%, approximately 5%, approximately 5.1%, approximately 5.2%, approximately 5.3%, approximately 5.4%, approximately 5.5%, approximately 5.6%, approximately 5.7%, approximately 5.8%, approximately 5.9%, approximately 6%, approximately 6.1%, approximately 6.2%, approximately 6.3%, approximately 6.4%, approximately 6.5%, approximately 6.6%, approximately 6.7%, approximately 6.8%, and approximately 6.9%.

[0213] 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. The antifoaming agent may be present in an amount of up to about 0.5% by weight of the coating composition in a given embodiment, and in an amount of about 0.1% to about 0.4% by weight of the coating composition in a given embodiment. In a given embodiment, the antifoaming agent is present in an amount greater than about 0% to about 3% by dry weight of the coat. In another embodiment, the antifoaming agent is present in an amount of about 0.4% to about 2% by dry weight of the coat. In yet another embodiment, the antifoaming agent is present in an amount of about 0.8% to about 1.5% by dry weight of the coat; for example, in amounts of 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 a given embodiment, the antifoaming agent is present in the coating formulation in an amount of about 0% to about 1.2% of the dry weight of the tablet; in another embodiment, in an amount of about 0% to about 0.8% of the dry weight of the tablet; and in yet another embodiment, in an amount of about 0% to about 0.2% of the dry weight of the tablet; for example, in an amount of 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.

[0214] The inclusion of an emulsifying agent (also called an emulsifier or emulgent) can promote actual emulsification during coat manufacturing and also provide emulsion stability throughout the shelf life of the product. Emulsifiers useful for the coat composition include, but are not limited to, natural materials and their semi-synthetic derivatives, such as polysaccharides, as well as glycerol esters, cellulose ethers, sorbitan esters, and polysorbates. Mixtures may be used. In at least one embodiment, the emulsifier used is polysorbate 80 (polyoxyethylene sorbitan mono-oleate) (e.g., Tween® 80). If present, the emulsifier or emulsifying agent may be present in an amount greater than 0% to about 0.5% by weight of the coat composition in a given embodiment. 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 a specific embodiment, the emulsifier is present in an amount greater than about 0% to about 2% of the dry weight of the coat. In another embodiment, the emulsifier is present in an amount greater than about 0.1% to about 1% of the dry weight of the coat. In yet another embodiment, the emulsifier is present in an amount greater than about 0.25% to about 0.75% of the dry weight of the coat; for example, in amounts of 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% of the dry weight of the coat. In a specific embodiment, the emulsifier is present in an amount greater than about 0% to about 0.8% of the dry weight of the tablet; in another embodiment, in an amount greater than about 0% to about 0.4% of the dry weight of the tablet; And in another embodiment, in an amount greater than about 0% to about 0.2% by 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.It is present in the coating formulation in amounts of 11%, approximately 0.12%, approximately 0.13%, approximately 0.14%, approximately 0.15%, approximately 0.16%, approximately 0.17%, approximately 0.18%, and approximately 0.19%.

[0215] Any colorant permitted in a film coat formulation is invariably a water-insoluble colorant (pigment). Pigments have certain advantages over water-soluble colorants in that they are chemically more stable to light, provide better opacity and coverage, and tend to optimize the impermeability of a given film to water vapor. Examples of suitable colorants include, but are not limited to, iron oxide pigments, titanium dioxide, and aluminum phosphates. Mixtures may be used. In at least one embodiment, the pigment or colorant used is titanium dioxide. The pigment or colorant, if present, may be present in an amount of about 0.1% to about 10% by weight of the coat composition in a given embodiment. In at least one embodiment, the colorant is present in an amount of about 0.1% to about 5% by weight of the coat 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 coat composition. In a given embodiment, the colorant is present in an amount greater than about 0% to about 20% by dry weight of the coat. In another embodiment, the colorant is present in an amount greater than about 0% to about 10% of the dry weight of the coat. In yet another embodiment, the colorant is about 2.2% to about 6.2% of the dry weight of the coat; For example, based on the dry weight of the coat, approximately 2.3%, approximately 2.4%, approximately 2.5%, approximately 2.6%, approximately 2.7%, approximately 2.8%, approximately 2.9%, approximately 3%, approximately 3.1%, approximately 3.2%, approximately 3.3%, approximately 3.4%, approximately 3.5%, approximately 3.6%, approximately 3.7%, approximately 3.8%, approximately 3.9%, approximately 4%, approximately 4.1%, approximately 4.2%, approximately 4.3%, approximately 4.4%, approximately 4.5%, approximately 4.6%, approximately 4.7%, approximately 4.8%, approximately 4.9%, approximately 5%, approximately 5.1%, approximately 5.2%, approximately 5.3%, approximately 5.4%, approximately 5.5%, approximately 5.6%, approximately It exists in amounts of 5.7%, approximately 5.8%, approximately 5.9%, approximately 6%, and approximately 6.1%.In a given embodiment, the coloring agent is present in the coating formulation in an amount greater than about 0% to about 8% of the dry weight of the tablet; in another embodiment, in an amount greater than about 0% to about 5% of the dry weight of the tablet; and in yet another embodiment, in an amount greater than about 0% to about 1% of the dry weight of the tablet; for example, in an amount of 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.

[0216] In at least one embodiment, the second excipient in the control-release coating comprises at least one neutral ester copolymer without any functional group (e.g., Eudragit® NE30D, Eudragit® NE40D, Eudragit® NM30D, Kollicoat® EMM30D, or a mixture 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 a mixture thereof), simethicone, polysorbate 80, titanium dioxide, and a mixture thereof.

[0217] 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 on water. In at least one embodiment, the controlled-release dosage form provides controlled-release of an effective amount of an active drug to at least one area of ​​the patient's upper gastrointestinal tract (e.g., stomach) when administered orally to a patient.

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

[0219] The coating composition may be applied onto a core containing an effective amount of therapeutic active agent by a process comprising the atomization (spraying) of the coating composition (solution or suspension) onto the bed of a tablet core. 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 devices operating according to the fluid bed principle include AEROMATIC™ (Fielder, Switzerland and UK) and GLATT AG™ (Switzerland). In at least one embodiment, the device used is ACCELA COTA®.

[0220] The coating composition is transferred from a peristaltic pump to a coating device at a desired speed and sprayed onto a rotary or fluidized tablet core. The tablet core is preheated to approximately 30°C. During the coating process, the product temperature range is maintained between approximately 25°C and approximately 35°C by adjusting the flow rates of the inlet and outlet air, the temperature of the inlet air, and the spraying speed. A single layer of the coating composition is applied, and once spraying is complete, the coated tablet core is dried at a temperature between approximately 30°C and approximately 40°C for approximately 3 to 5 minutes at a low fan speed and low air flow. The fan is readjusted to a jog speed, and drying is continued for approximately 12 to 15 minutes.

[0221] The coated tablet core is placed on a tray and cured (heat treatment after coating) in an electric or steam oven at a temperature higher than the melting point of polyethylene glycol or its derivative. In at least one embodiment, the curing temperature is higher than the melting point of polyethylene glycol or its derivative. In at least one embodiment, the curing time is about 2 to about 7 hours. The cured coated tablet is subsequently cooled to approximately room temperature.

[0222] In a specific other embodiment, the coated tablet core is 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., about 50°C to about 59°C in a specific embodiment) for a specified time period (e.g., about 15 minutes to about 90 minutes in a specific embodiment; and about 60 minutes in at least one embodiment). During the second stage, the coated tablet is cured at a second curing temperature above the melting point of polyglycol (e.g., about 60°C to about 70°C in a specific embodiment) for an additional time period (e.g., about 30 minutes to about 180 minutes in a specific embodiment; and about 120 minutes in at least one embodiment). In at least one embodiment, the two-stage curing of the coated tablet reduces non-functional defects in the tablet caused by the curing process. In at least one embodiment, the two-stage curing process substantially eliminates non-functional defects in the tablet caused by the curing process. Non-functional defects in the formulation resulting from the curing process may include visual defects of the coating (e.g., poor color uniformity and / or a blurry appearance), defects of the coating surface (e.g., surface roughness and / or wrinkling of the coating), and tablets sticking to each other and / or the coating pan. Additionally, defects in the color and smoothness of the tablets are reduced, thereby improving the printability of the tablets.

[0223] In some embodiments, the coating formulation is used to coat various calcium alpha-ketoglutarate cores and can be adjusted to obtain a desired drug release profile. The length and time of the delay are controlled by the hydration rate and the thickness of the coat. The drug release rate after the delay is determined by the thickness and permeability of the hydrated coat. Thus, it is possible to adjust the hydration rate and permeability of the coat so that a desired controlled-release drug profile can be achieved. There is no preferred coat thickness, as it depends on the drug used in the core and also on the desired controlled-release profile.

[0224] Other parameters combined with the coat thickness include varying the concentration of certain components of the stable coat composition and / or varying the curing temperature and length for curing the coated tablet core. A skilled technician would know which parameters or combinations of parameters to change for the desired controlled-release profile.

[0225] Immediate-release coating formulation

[0226] In some embodiments, the immediate-release coating comprises calcium alpha-ketoglutarate and additional agents described herein. In some embodiments, an effective amount of the immediate-release active agent in the immediate-release form is coated onto the formulation described herein. For example, if the extended release of calcium alpha-ketoglutarate from the formulation is due to the controlled-release coating, an immediate-release layer of the additional agent will be overcoated on top of the controlled-release coating. In some embodiments, an immediate-release layer of the additional agent is coated onto the surface of a substrate in which calcium alpha-ketoglutarate is incorporated into a controlled-release substrate. When a plurality of sustained-release substrates (e.g., a multiply particle system including pellets, spheres, beads, etc.) containing an effective unit dose of calcium alpha-ketoglutarate are incorporated into a hard gelatin capsule, the side effect-reducing compound may be incorporated into the gelatin capsule by including a sufficient amount of an immediate-release antihistamine or antiemetic as a powder or granule within the capsule. Alternatively, the gelatin capsule itself can be coated with an immediate-release layer of an additional formulation.

[0227] A final dosage form can be created by adding a coating containing the immediate release of an additional agent, such as an antihistamine or antiemetic, to the outside of a controlled-release tablet core. Such a coating can be prepared by mixing a compound such as promethazine with polyvinylpyrrolidone (PVP) 29 / 32 or hydroxypropyl methylcellulose (HPMC) and water / isopropyl alcohol and triethyl acetate. Such an immediate-release coating can be spray-coated onto the tablet core. The immediate-release coating may also be applied using a press-coating process with a blend consisting of 80 wt% promethazine and 20 wt% lactose and hydroxypropyl methylcellulose type 2910.

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

[0229] Formulation and Route of Administration

[0230] The sustained-release compositions of calcium alpha-ketoglutarate disclosed herein may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the processing of the active compound into formulations that can be used pharmaceutically. The appropriate formulation depends on the selected route of administration. Further details regarding excipients suitable for the compositions described herein are provided in, for example, the literature [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, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. It can be found in [Lippincott Williams & Wilkins 1999], and these documents are cited by reference for such disclosures.

[0231] The composition of calcium alpha-ketoglutarate described herein is administered to a subject by a number of routes of administration, including oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, inhalation, buccal, topical, rectal, or transdermal administration. In some embodiments, the composition described herein containing calcium alpha-ketoglutarate is formulated into any suitable form of administration, 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, rapid-dissolving formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, coated tablets, capsules, delayed-release formulations, extended-release formulations, pulsed-release formulations, multiply particulate formulations, and immediate-release and controlled-release mixed formulations.

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

[0233] In some embodiments, the composition for oral use is a tablet (including suspension tablets, rapid-dissolving tablets, bite-disintegration tablets, rapid-disintegrating tablets, effervescent tablets, or coated tablets), a pill, a powder (including sterile packaged powder, dispenseable powder, or effervescent powder), a capsule (soft and hard capsules, e.g., capsules made of animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), a solid dispersion, a solid solution, a biodegradable dosage form, a controlled-release formulation, a pulsed-release dosage form, a multi-particle dosage form, a pellet, a granule, or an aerosol. In some embodiments, the composition for oral use is a solid dosage form, e.g., a tablet, an effervescent tablet, and a 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 such a bulk blend composition is referred to as homogeneous, it means that the particles of calcium alpha-ketoglutarate are evenly dispersed throughout the composition so that the composition can be further divided into uniformly effective unit dosage forms, e.g., tablets, pills, and capsules. Individual unit doses may also include a film coating that degrades upon oral intake or contact with a diluent.

[0234] For oral administration, the composition disclosed herein may be easily formulated by combining the active compound(s) with a pharmaceutically acceptable carrier known in the art. Such a carrier may enable the composition disclosed herein to be formulated for oral intake by a patient to be treated as a tablet, pill, coated tablet, capsule, lozenge, hard candy, liquid, gel, syrup, slurry, powder, suspension, elixir, wafer, etc., including chewable tablets. Such formulations may include a pharmaceutically acceptable carrier comprising a solid diluent or filler, a sterile aqueous medium, and various non-toxic organic solvents. Generally, the composition disclosed herein will be included at a concentration level in the range of about 0.5%, about 5%, about 10%, about 20%, or about 30% to about 50%, about 60%, about 70%, about 80%, or about 90% by weight of the total composition in an oral dosage form, in an amount sufficient to provide a preferred dosage unit.

[0235] Additional sanctions

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

[0237] In some embodiments, the composition includes a vitamin. In some embodiments, the vitamin is vitamin A, vitamin B, vitamin C, or vitamin D.

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

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

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

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

[0242] 실시예

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

[0244] Example 1. General manufacturing procedure for calcium alpha-ketoglutarate sustained-release tablets. An exemplary tablet contains 350 to 450 mg of alpha-ketoglutarate by weight based on free acid. Additionally, an exemplary tablet contains 450 to 650 mg of alpha-ketoglutarate by weight based on salt and hydrate forms. Additionally, an exemplary tablet contains 150 to 250 mg of calcium by weight when alpha-ketoglutarate is a calcium salt. Uncoated tablets have an average weight of about 1,000 to 1,000 mg, containing about 1,030 mg. Coated tablets have an average weight of about 1,020 to 1,120 mg, containing about 1,060 mg. An exemplary tablet core comprises the following:

[0245]

[0246]

[0247] Exemplary coatings include the following:

[0248]

[0249] calculate

[0250] For example, calcium alpha-ketoglutarate monohydrate corresponds to the following:

[0251] Alpha-ketoglutarate = 350 mg;

[0252] Conversion factor = 1.26 (for alpha-ketoglutarate anhydrous);

[0253] Amount after conversion = 441 mg;

[0254] Std LOD = 10%; Standard Test = 98%;

[0255] Standard calculation: (441×100×100) / (98×(100-10)) = 500 mg;

[0256] It also contains elemental calcium = 19.5 to 22%;

[0257] Considering the minimum value = 19.5%;

[0258] 500 mg CAKG contains 97.5 mg of elemental calcium.

[0259] Standard manufacturing procedures

[0260] 1. Weighing

[0261] Weigh all ingredients according to the amounts given in the formula.

[0262] 2. Selection

[0263] 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. Subsequently, 2500.0 gm of calcium alpha-ketoglutarate monohydrate is blended for 2 minutes and sieved through a #30 sieve. 50.0 gm of colloidal silicon dioxide is sieved through a #40 sieve, and 50.0 gm of magnesium stearate is sieved through a #60 sieve. Each sieved material is collected individually in a polybag. (The temperature and RH must be NMT 27°C and 40% RH during this process.)

[0264] 3. Mixing and Granulation

[0265] The above-mentioned selected ingredients (HPMC K4 and HPMC K15, calcium alpha-ketoglutarate monohydrate, lactose monohydrate, colloidal silicon dioxide, and microcrystalline cellulose) are mixed in a double cone blender (18 liter capacity) at 16 rpm for 25 minutes. Magnesium stearate is added to the blend and mixed in a double cone blender (18 liter capacity) for 5 minutes.

[0266] 4. Slugging

[0267] Tablets are obtained by slugging the dry mixed material obtained in the previous step using a press with a suitable punch size. Punch description: 196×8.4 mm, capsule shape, standard concave type, plain punch. Hardness: 2 to 5 kg / cm² .

[0268] 5. Deslugging

[0269] The tablets are milled using a 6.0 mm SS screen and an 18# sieve for final granular sizing. Note: (Slugging and deslugging must be performed twice to obtain granules with suitable flow characteristics).

[0270] Deslugged granule parameters (target):

[0271] 1) Bulk density - 0.6 to 0.7 gm / mL;

[0272] 2) Tap density - 0.9 to 1.0 gm / ㎖;

[0273] 3) Carr's Index - 25 to 30%; and

[0274] 4) House width (Hausner Ratio) - 1.3 to 1.4.

[0275] 6. Lubrication

[0276] Check the integrity of the sieve before use. Sift 98.75 gm of colloidal silicon dioxide through a #40 sieve. Sift 86.25 gm of magnesium stearate through a #60 sieve. Mix the deslugged mass of Step 5 with the colloidal silicon dioxide in a double cone blender for 5 minutes. Add the magnesium stearate to the blend in a double cone blender for 5 minutes. Collect the lubricated granules in a double polyethylene bag, close it tightly, and store. In some embodiments, one or more of flavoring agents, vitamins, antioxidants, and sweeteners are added to the composition during the lubrication step together with the magnesium stearate and / or colloidal silicon dioxide.

[0277] 7. Pressing of tablets

[0278] Surrounding parameters:

[0279] 1) RH-NMT 40%;

[0280] 2) Temperature - NMT 27℃;

[0281] Air pressure difference - NLT 10 Pascals;

[0282] *Punch type: 'D' tooling;

[0283] 19.6×8.4 mm, capsule shape, standard concave shape. Plain punch.

[0284] After turning the hand wheel, check the complete rotation of the turret using electric operation. Feed the granules and set the machine according to the desired specifications. Check the tablets from one complete rotation.

[0285] 8. Film coating of tablets

[0286] Instamoistshield white (ICMS 2398) is added to disperse it in a given amount of isopropyl alcohol under stirring. Stirring is continued for 5 minutes. Under continued stirring, methylene chloride is added to the given amount from the previous step and stirred further for 40 to 45 minutes to obtain a white, viscous, lump-free suspension. The suspension is passed through a colloid mill for 15 minutes at "O" adjustment intervals. The coating suspension is filtered through a 200 mesh nylon cloth. The exhaust device is turned on, and the film-coating suspension is applied to the tablets using a clean spray gun assembly (ensuring good appearance), while continuously stirring the coating suspension during tablet coating. After an appropriate weight gain (300%), the film-coated tablets are thoroughly dried. Target average weight of film-coated tablets = 1060.0 mg. Once the target weight gain is achieved, the film-coated tablets are dried in a coating pan for 30 minutes.

[0287] Example 2. Solubility profile of sustained release of calcium alpha-ketoglutarate

[0288] [Solution Parameters]

[0289] Medium: 900 ml enzyme-free simulated gastric juice (SGF)

[0290] Device: Paddle (equipped with sinker)

[0291] Speed: 75 rpm

[0292] Hours: 1st hour, 4th hour, 8th hour and 12th hour.

[0293] [Chromatography Conditions]

[0294] Column: Inertsil ODS, 3V (250×4.6㎜) 5 µm or equivalent;

[0295] Flow rate: 0.8 ml / min

[0296] Wavelength: 210 nm

[0297] Injection volume: 10 uL

[0298] Oven temperature: 30℃

[0299] Sample cooler temperature: 15℃

[0300] Yongli Mode: Deungyongmae

[0301] Enzyme-free simulated gastric juice (SGF). (Dissolution medium): Weigh 2.0 gm of sodium chloride and 7.0 ml of concentrated hydrochloric acid, transfer to 1000 ml of water, and mix.

[0302] Buffer solution: Dissolve 2.72 gm of potassium dihydrogen orthophosphate in 1000 ml of water and add 2.0 ml of orthophosphate.

[0303] Mobile phase: Prepare a mixture of 95 volumes of buffer and 5 volumes of acetonitrile mix, and degas the filter before use.

[0304] Standard solution: Accurately weigh 55 mg of calcium alpha-ketoglutarate working standard, transfer it to a 100 ml dry quantitative flask, and add 50 ml of dissolution medium. Dissolve this volume in the solvent medium and prepare and mix.

[0305] Test solution: Set the dissolution parameters and place one tablet in each container to remove air bubbles from the surface of the tablet, and immediately start the device. After the 1st, 4th, 8th, and 12th hours, withdraw 10 ml of the sample of the medium and replace this with new fluid. Filter the withdrawn sample through a 0.45-micron nylon syringe filter; pour off the first few ml of the filtrate.

[0306] System suitability: Inject five repeated injections of the standard solution. The relative standard deviation for repeated injections is 2% or less.

[0307] Procedure: Inject 10 µL of each test solution into a liquid chromatograph and record the chromatogram. Measure the reaction for the calcium alpha-ketoglutarate peak. Calculate the percentage of drug release of calcium alpha-ketoglutarate from the peak area of ​​the calcium alpha-ketoglutarate of the standard and test the percentage of titer of the working standard used.

[0308]

[0309] calculate:

[0310] (AT / AS)×(W / 100)×(900 / LC)×(p / 100)×100

[0311] Here,

[0312] AT - Peak area of ​​calcium alpha-ketoglutarate in the chromatogram obtained from each test solution injection;

[0313] AS - Peak area of ​​calcium alpha-ketoglutarate in the chromatogram obtained from five repeated injections of standard solution;

[0314] WS - Weight of calcium alpha-ketoglutarate working standard in mg; LC - Label claim;

[0315] P - Potency of calcium alpha-ketoglutarate working standard against these criteria.

[0316] Correction factor:

[0317] (Volume removed in previous time interval × Dissolved % (indicated %)) / Volume of dissolution medium

[0318] For the first hour point = % dissolved after 1 hour;

[0319] For the 4th hour point = % dissolved after 1 hour + % dissolved after 4 hours;

[0320] For the 8th hour point = Correction factor for the 1st hour + Correction factor for the 4th hour + % dissolved after the 8th hour;

[0321] For the 12th hour point = Correction factor for the 1st hour + Correction factor for the 4th hour + Correction factor for the 8th hour + % dissolved after the 12th hour;

[0322] result:

[0323]

[0324]

[0325] Although preferred embodiments of the present disclosure have been illustrated and described herein, it will be apparent to those skilled in the art that such embodiments are provided merely as examples. Numerous variations, changes, and substitutions will now come to mind for 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 when practicing the invention. The following claims define the scope of the present disclosure and are intended to encompass methods, structures, and equivalents thereof that fall within the scope of such claims.

[0326] Method Example 1. Increase in healthy lifespan and / or lifespan of mice. Non-genetically modified mice aged 18 months are fed a control diet, optionally a control diet with an immediate-release formulation added (positive control), or a control diet with the composition described herein added (treatment group). Mice are allowed to die naturally without being sacrificed. The lifespan of the mice is compared between the treatment group and the control group, and optionally between the positive control. In addition to determining lifespan, senescence of the mice is determined throughout the study by a non-invasive senescence index consisting of 31 observations selected from clinically relevant senescence indices. The composition described herein improves lifespan, healthy lifespan, and / or senescence in both sexes compared to the control and positive control. For further details regarding the examples, see the literature [Lucanic, M., Lithgow, GJ, & Alavez, S. (2013). Pharmacological lifespan extension of invertebrates. Ageing research reviews , 12 (1), 445-458; Searle, S. D., Mitnitski, A., Gahbauer, E. A., Gill, T. M., & Rockwood, K. (2008). A standard procedure for creating a frailty index. BMC geriatrics , 8 (1), 24; and Whitehead (2014.)] is described.

[0327] Method Example 2. Increase in healthy lifespan and / or lifespan in humans (males and females). The compositions described herein are administered orally or parenterally to male and female volunteers and are compared to a control group administered a placebo, and optionally to a positive control group administered a commercially available Ca-AKG, such as immediate-release Ca-AKG. Volunteers are monitored for lifespan, healthy lifespan, and frailty using at least one of the usual 31 frailty index observations. The study is an open-label study comparing a treatment group with a control group, and optionally a positive control group. Volunteers are evaluated at three time points: study start (Day 1), 3 months, and 6 months. At each visit, blood pressure, heart rate, weight, safety lab, CRP, blood chemistry, hemoglobin A1C, and uric acid levels are obtained, and a study questionnaire is completed by each participant.

[0328] Blood chemistry, for example, is referenced in the literature [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 It is used to calculate the biological age of a participant by one or more published algorithms, as described in

[30] E4104-E4110].

[0329] In one exemplary study design, participants are assigned to a control group, an optional positive control group, or a treatment group, and each participant takes two tablets daily for six months. The control group takes a placebo, the positive control group takes an immediate-release formulation, and the treatment group takes two tablets as follows:

[0330] Male: A tablet comprising 500 mg of calcium alpha-ketoglutarate monohydrate; 450 mcg of retinyl palmitate; and one or more release-controlling agents;

[0331] Women: Tablets comprising 500 mg of calcium alpha-ketoglutarate monohydrate; 12.5 mcg (500 IU) of cholecalciferol; and one or more release-controlling agents.

[0332] One or more primary outcomes are evaluated for each group. Primary outcomes are determined by evaluating the following vital signs and blood chemistry:

[0333]

[0334]

[0335]

[0336]

[0337]

[0338] Reference by reference

[0339] All disclosed publications, patents, and patent applications are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated as being incorporated by reference.

Claims

Claim 1 A pharmaceutical formulation comprising (a) calcium alpha-ketoglutarate and (b) a controlled-release matrix, wherein the controlled-release matrix comprises one or more hydroxypropylmethylcellulose (HPMC) selected from the group consisting of HPMC with a number average molecular weight in the range of 68,000 to 95,000, HPMC with a number average molecular weight in the range of 115,000 to 150,000, or a combination thereof. Claim 2 A pharmaceutical formulation according to claim 1, wherein the control-release substrate comprises a combination of a first HPMC having a number average molecular weight of 68,000 to 95,000 and a second HPMC having a number average molecular weight of 115,000 to 150,000. Claim 3 A pharmaceutical formulation according to claim 1 or 2, wherein the amount of calcium alpha-ketoglutarate is 30% to 65% of the total weight. Claim 4 A pharmaceutical formulation according to claim 1 or 2, further comprising microcrystalline cellulose. Claim 5 A pharmaceutical formulation according to claim 1 or 2, further comprising lactose monohydrate. Claim 6 A pharmaceutical formulation according to claim 1 or 2, further comprising one or more lubricants, one or more disintegrants, one or more sweeteners or one or more waxes, or any combination thereof. Claim 7 A pharmaceutical formulation according to claim 1 or 2, characterized in that the release rate of calcium alpha-ketoglutarate is 90% or less of the release rate of calcium alpha-ketoglutarate of a calcium alpha-ketoglutarate formulation formulated without an uncontrolled or controlled-release substrate. Claim 8 A pharmaceutical formulation according to claim 1 or 2, characterized in that the release rate of calcium alpha-ketoglutarate is 30% or less after a time of 0.5 to 2 hours in a dissolving medium as measured by a paddle device while the basket is rotated at 75 rpm, and the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at 37°C. Claim 9 A pharmaceutical formulation according to claim 1 or 2, characterized by a release rate of calcium alpha-ketoglutarate of 75% or more after 10 to 11 hours in a dissolving medium as measured by a paddle device while the basket is rotated at 75 rpm, wherein the dissolving medium is 900 ml of 0.03 M NaCl and 0.08 M HCl at 37°C. Claim 10 A pharmaceutical formulation according to claim 1 or 2, comprising 250 mg to 1000 mg of calcium alpha-ketoglutarate and in the form of a unit dose. Claim 11 In item 10, the above unit dosage form is a pharmaceutical formulation configured for oral administration. Claim 12 In paragraph 11, the above unit dosage form is a tablet, a pharmaceutical formulation. Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete

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