Medium chain triglyceride formulations with improved bioavailability and methods related thereto

Abstract

The present invention relates to compositions of medium chain triglycerides (MCTs) and to therapeutic methods of treating conditions associated with reduced neuronal metabolism, such as Alzheimer's disease, with such compositions.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application date of March 4, 2020, application number 202080018523.2, and invention name “Medium chain triglyceride preparations with improved bioavailability and related methods”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 813,448, filed on March 4, 2019, and U.S. Provisional Application No. 62 / 837,136, filed on April 22, 2019, the disclosures of each of which are hereby incorporated by reference in their entireties. Technical Field

[0004] The present disclosure relates to pharmaceutical compositions comprising high drug loadings of medium chain triglycerides in the presence or absence of protein, and methods of making and using such compositions. Background Art

[0005] Medium chain triglycerides (MCT) are composed of fatty acids with a chain length of 5-12 carbons. MCT has been extensively studied and has known nutritional and pharmaceutical uses. MCT has a melting point that is liquid at room temperature. In addition, MCT is relatively small and ionizable under physiological conditions and is generally soluble in aqueous solutions.

[0006] When intended for use as a pharmaceutical composition, it is often desirable to achieve specific pharmacokinetic properties (e.g., C max , T max wait).

[0007] Therefore, there is a need in the art for pharmaceutical compositions of MCTs that achieve specific pharmacokinetic properties. Summary of the invention

[0008] In one aspect, the present disclosure relates to a method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the substantial absence of protein, the MCT composition provides a maximum concentration (C ) of total ketones for at least 3 hours after administration. max In certain embodiments, the C max is the maximum serum concentration of total ketones. In certain embodiments, the MCT composition provides a maximum serum concentration of total ketones (C ) within at least 2.5 hours after administration, at least 2 hours after administration, at least 1.5 hours after administration, or at least 1 hour after administration. maxIn certain embodiments, the therapeutically effective amount of MCT is 20 g and the total ketone content is C max In some embodiments, the MCT pharmaceutical composition is stable at a pH of about 1 to about 3.

[0009] In one aspect, the present disclosure relates to a method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the substantial absence of protein, the MCT composition provides a maximum concentration (C 2 + 400 mg / kg) of b-hydroxybutyrate (BHB) for at least 3 hours after administration. max In certain embodiments, the C max is the maximum serum concentration of BHB. In certain embodiments, the MCT composition provides a maximum serum concentration (C ) of BHB within at least 2.5 hours after administration, at least 2 hours after administration, at least 1.5 hours after administration, or at least 1 hour after administration. max In certain embodiments, the therapeutically effective amount of MCT is 20 g and the C of BHB is max In some embodiments, the MCT pharmaceutical composition is stable at a pH of about 1 to about 3.

[0010] In one aspect, the present disclosure relates to a method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the substantial absence of protein, the MCT composition provides a maximum concentration (C ) of acetoacetate (AcAc) for at least 2.5 hours after administration. max In certain embodiments, the C max is the maximum serum concentration of AcAc. In certain embodiments, the MCT composition provides a maximum serum concentration (C ) of AcAc within at least 2 hours after administration, at least 1.5 hours after administration, or at least 1 hour after administration. max In certain embodiments, the therapeutically effective amount of MCT is 20 g and the C of AcAc is maxAt least 50umol / L, at least 60umol / L, at least 70umol / L, at least 80umol / L, at least 90umol / L or at least 100umol / L. In certain embodiments, the MCT pharmaceutical composition is stable at a pH of about 1 to about 3.

[0011] In one aspect, the present disclosure relates to a method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the presence of protein, the MCT composition provides a maximum concentration of total ketones (C 60 mmol / l) for at least 2.5 hours after administration. max In certain embodiments, the C max is the maximum serum concentration of total ketones. In certain embodiments, the MCT composition provides a maximum serum concentration of total ketones (C ) at least 3.0 hours after administration, at least 3.5 hours after administration, at least 4.0 hours after administration, or at least 5 hours after administration. max In certain embodiments, the therapeutically effective amount of MCT is 20 g and the total ketone content is C max In some embodiments, the MCT pharmaceutical composition is stable at a pH of about 5 to about 7.

[0012] In one aspect, the present disclosure relates to a method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the presence of protein, the MCT composition provides a maximum concentration (C 200 of β-hydroxybutyrate (BHB) at least 2.5 hours after administration. max In certain embodiments, the C max is the maximum serum concentration of BHB. In certain embodiments, the MCT composition provides a maximum serum concentration (C ) of BHB at least 3.0 hours after administration, at least 3.5 hours after administration, at least 4.0 hours after administration, or at least 5 hours after administration. max In certain embodiments, the therapeutically effective amount of MCT is 20 g and the C of BHB is max In some embodiments, the MCT pharmaceutical composition is stable at a pH of about 5 to about 7.

[0013] In one aspect, the present disclosure provides a method of treating a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the presence of protein, the MCT composition provides a maximum concentration (C 60.35) of acetoacetate (AcAc) at least 2.5 hours after administration. max In certain embodiments, the C max is the maximum serum concentration of AcAc. In certain embodiments, the MCT composition provides a maximum serum concentration (C ) of AcAc at least 3.0 hours after administration, at least 3.5 hours after administration, at least 4.0 hours after administration, or at least 5 hours after administration. max In certain embodiments, the therapeutically effective amount of MCT is 20 g and the C of AcAc is max At least 20umol / L, at least 25umol / L, at least 30umol / L, at least 35umol / L, or at least 40umol / L. In certain embodiments, the MCT pharmaceutical composition is stable at a pH of about 5 to about 7.

[0014] In one aspect, the disclosure provides a method for treating a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCT), wherein the therapeutically effective amount of MCT is administered in two parts, wherein the first part comprises a first therapeutically effective amount of medium chain triglycerides (MCT), which is substantially released within 3 hours after being administered to the subject, and wherein the second part comprises a second therapeutically effective amount of medium chain triglycerides (MCT) and protein, wherein the second amount of MCT is substantially released from the second part after the second part is administered to the subject for 3 hours or more. In certain embodiments, the MCT of the first part is administered in the absence of substantially any protein. In certain embodiments, the MCT of the first part is substantially released within 2.5 hours, within 2 hours, within 1.5 hours, or within 1 hour after being administered to the subject. In certain embodiments, the MCT of the second part is substantially released after being administered to the subject for 3.5 or more hours, 4 or more hours, 4.5 or more hours, or 5 or more hours.

[0015] In certain embodiments of the disclosed methods, the disease or disorder is a disease or disorder associated with decreased cognitive function. In certain embodiments of the disclosed methods, the disease or disorder associated with decreased cognitive function is selected from Alzheimer's disease and age-related memory impairment. In certain embodiments of the disclosed methods, the subject lacks an ApoE4 genotype. In certain embodiments of the disclosed methods, the subject is a human.

[0016] In certain embodiments of the disclosed methods, the amount of total ketones, BHB and / or AcAc is determined using an enzymatic method.

[0017] In another aspect, the disclosure provides a pharmaceutical composition comprising a first component and a second component, wherein the first component comprises a therapeutically effective amount of a first portion of medium chain triglycerides (MCTs) that are substantially released within 3 hours after the pharmaceutical composition is administered to a subject in need thereof, and wherein the second component comprises a therapeutically effective amount of a second portion of medium chain triglycerides (MCTs) and proteins, wherein the second portion of MCTs is substantially released from the second component within 3 hours or more after the pharmaceutical composition is administered to the subject. In certain embodiments, the MCTs of the first portion are substantially released within 2.5 hours, within 2 hours, within 1.5 hours, or within 0.5 hours of the administration of the pharmaceutical composition.

[0018] In one aspect, the present disclosure provides a pharmaceutical composition comprising: a medium chain triglyceride (MCT) and at least one pharmaceutically acceptable excipient, wherein the composition is substantially free of protein, wherein when administered to a subject in need thereof 30 minutes after a standard meal and in the substantial absence of protein, the composition provides a maximum concentration (C 60 of at least one ketone body) for at least 3 hours after administration. max In certain embodiments, the C max is the maximum serum concentration of at least one ketone body. In certain embodiments, the MCT composition provides a maximum serum concentration (C ) of at least one ketone body within at least 2.5 hours after administration, at least 2 hours after administration, at least 1.5 hours after administration, or at least 1 hour after administration. max ). The at least one ketone body may be b-hydroxybutyrate (BHB), acetoacetate (AcAc), or a combination thereof.

[0019] In certain embodiments, the disclosed MCT pharmaceutical composition is an emulsion. In certain embodiments, the emulsion does not phase separate for at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 5 hours, or at least 24 hours. In certain embodiments, the emulsion has an average droplet diameter of about 100 nm to about 1000 nm, about 100 nm to about 500 nm, or about 200 nm to about 300 nm.

[0020] In certain embodiments, the disclosed MCT pharmaceutical composition comprises at least 95% tri:C8 MCT (tri:C8 MCT). In certain embodiments, the MCT pharmaceutical composition comprises at least 98% tri:C8 MCT.

[0021] In certain embodiments, the disclosed MCT pharmaceutical compositions comprise at least 95% caprylic triglyceride. In certain embodiments, the MCT pharmaceutical compositions comprise at least 98% caprylic triglyceride.

[0022] Although multiple embodiments are disclosed, other embodiments of the present disclosure will become apparent to those skilled in the art from the following detailed description which shows and describes exemplary embodiments of the present disclosure. It will be appreciated that the present invention is capable of being varied in various aspects without departing from the spirit and scope of the present disclosure. Therefore, the detailed description should be regarded as exemplary and non-limiting in nature. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Shown is a graph measuring serum levels of beta-hydroxybutyrate (BHB) versus time in blood samples after oral administration of one of four MCT-containing formulations.

[0024] Figure 2 Shown is a graph of the pharmacokinetic (PK) level differences versus time (hours) measuring serum total ketone levels in blood samples following oral administration of MCT+water, MCT+Ensure, and MCT+Protein.

[0025] Figure 3A Shown are graphs of baseline adjusted total ketone levels in serum measured in each cohort versus time following administration of a 20 g dose of MCT with and without food.

[0026] Figure 3B Shown is a graph of total ketone levels observed in serum measured in each cohort versus time following administration of a 20 g dose of MCT with and without food.

[0027] Figure 3C Shown is a graph of baseline adjusted beta-hydroxybutyrate (BHB) levels in serum measured in each cohort versus time following administration of a 20 g dose of MCT with and without food.

[0028] Figure 3D Shown is a graph of beta-hydroxybutyrate (BHB) levels observed in serum measured in each cohort versus time following administration of a 20 g dose of MCT with and without food.

[0029] Figure 3E Shown are graphs of baseline adjusted acetoacetate (AcAc) levels in serum measured in each cohort versus time following administration of a 20 g dose of MCT with and without food.

[0030] Figure 3F Shown is a graph of acetoacetate (AcAc) levels observed in serum measured in each cohort versus time following administration of a 20 g dose of MCT with and without food.

[0031] Figure 4A Shown is a graph of mean serum total ketone concentrations observed from an enzyme assay measured in a protein-based MCT formulation versus time relative to a non-protein-based MCT formulation.

[0032] Figure 4B Shown is a graph of mean serum total ketone baseline adjusted concentration versus time measured in protein-based MCT formulations relative to non-protein-based MCT formulations observed from enzyme assays.

[0033] Figure 5 The table shown indicates the total ketone concentrations observed from the enzymatic assay in protein-based MCT formulations relative to non-protein-based MCT formulations.

[0034] Fig. 6A Shown is a graph of mean serum beta-hydroxybutyrate (BHB) concentrations observed from an enzyme assay measured in a protein-based MCT formulation versus time relative to a non-protein-based MCT formulation.

[0035] Figure 6B Shown is a graph of mean serum beta-hydroxybutyrate (BHB) baseline adjusted concentrations observed in protein-based MCT formulations measured relative to non-protein-based MCT formulations versus time.

[0036] Fig. 7A Shown is a graph of mean serum acetoacetate (AcAc) concentrations observed in protein-based MCT formulations versus time relative to non-protein-based MCT formulations.

[0037] Figure 7B Shown is a graph of mean serum acetoacetate (AcAc) baseline-adjusted concentrations observed in protein-based MCT formulations measured relative to non-protein-based MCT formulations versus time. DETAILED DESCRIPTION OF THE INVENTION

[0039] Several definitions are described herein. Such definitions are intended to encompass grammatical equivalents. Unless otherwise required by the context, singular terms used herein and in the claims should include plural, and plural terms should include singular. Unless otherwise specified, the use of "or" refers to "and / or". In addition, the use of the terms "comprise", "have", "include" and other forms (such as "comprises" and "containing") is intended to be inclusive and means that there may be additional elements in addition to the elements listed. In addition, unless otherwise specifically stated, terms such as "element" or "component" cover elements and components comprising a unit and elements and components comprising more than one subunit.

[0040] As background, medium chain triglycerides ("MCT") are metabolized in a different manner than more common long chain triglycerides (LCT). Specifically, when compared to LCT, MCT is more easily digested to release medium chain fatty acids (MCFA), which exhibit increased portal absorption rates and undergo obligate oxidation (obligate oxidation). Relative to LCT, the small size and reduced hydrophobicity of MCT increase the rate of digestion and absorption. When MCT are ingested, they are first processed by lipase, which cuts fatty acid chains from the glycerol backbone. Certain lipases before the duodenum preferentially hydrolyze MCT relative to LCT, and the released MCFA are then partially absorbed directly by the gastric mucosa. Those MCFA that are not absorbed in the stomach are absorbed directly into the portal vein and are not assembled into lipoproteins. Since blood transport is much faster than lymphatic transport, MCFA quickly reach the liver. Obligate oxidation occurs in the liver.

[0041] In contrast, long-chain fatty acids (LCFA) derived from normal dietary fat are re-esterified into LCT and packaged into chylomicrons for transport in the lymph. This greatly slows down the metabolism of LCT relative to MCT. In the fed state, LCFA is hardly oxidized in the liver, mainly due to the inhibitory effect of malonyl-CoA. When conditions are favorable for fat storage, malonyl-CoA is produced as an intermediate for lipogenesis. Malonyl-CoA allosterically inhibits carnitine palmitoyltransferase I, and thereby inhibits LCFA transport into mitochondria. This feedback mechanism prevents the ineffective cycle of lipolysis and lipogenesis.

[0042] MCFAs are largely unconstrained by the rules governing LCFA oxidation. MCFAs do not require the use of carnitine palmitoyltransferase I to enter the mitochondria, so MCFAs bypass this regulatory step and are oxidized regardless of the metabolic state of the organism. Importantly, since MCFAs quickly enter the liver and are rapidly oxidized, large amounts of ketone bodies are readily produced from MCFAs. Therefore, large oral doses of MCTs (e.g., about 20 mL to 40 mL) will result in sustained hyperketonemia.

[0043] In certain aspects of the present disclosure, it has been unexpectedly discovered that the bioavailability of MCT can be controlled by administering MCT with or without protein. Without intending to be limited, as shown herein, it has been discovered that MCT formulations containing or administered with protein provide a slow or delayed release of MCT compared to administration in a low protein / no protein setting. Protein-based formulations tend to delay and reduce the maximum (or peak) concentration ("C max ”). However, administration of a substantially protein-free MCT preparation or administration of MCT in the absence of protein allows maximization of C max and minimize to reach C max Time (“T max ”). In other embodiments, it was discovered that the bioavailability of MCTs and the in vivo formation of active metabolites, ketone bodies, can be optimized by selective formulation with and without protein carrier excipients.

[0044] In certain aspects, it has been unexpectedly discovered that improved MCT bioavailability and in vivo formation of active metabolites, ketone bodies, can be achieved using MCT preparations with low or no protein content. In this regard, the MCT preparations of the present disclosure can be prepared substantially without protein. In addition, the MCT preparations of the present disclosure can be administered substantially without protein.

[0045] As used herein, "administering" includes in vivo use environments, such as the gastrointestinal tract, delivery by ingestion or swallowing, or other such means of delivering a pharmaceutical composition, as understood by those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, 20th Edition (2000). When the aqueous use environment is in vitro, "administering" refers to the placement or delivery of a pharmaceutical composition in an in vitro test medium.

[0046] As used herein, the terms "substantially free of protein," "substantially free of protein," "no protein," "absence of protein," "substantially no protein present," and the like mean the absence of protein in an amount that would meaningfully interfere with the release of MCT. One skilled in the art will appreciate that trace amounts of protein (such as minor contamination) may be present during the administration of MCT or in an MCT preparation without affecting the overall release and metabolism of MCT, and without departing from the spirit of the present disclosure regarding preparation and administration under protein-free conditions. In addition, when an MCT preparation is described as being administered in the substantial absence of protein, this means that the MCT preparation itself is substantially free of protein, and that substantially no other protein is administered concurrently with the MCT preparation at the time of administration.

[0047] In certain embodiments, MCT formulations that substantially do not contain protein and / or are administered in the substantial absence of protein can provide a faster release of MCTs, with a higher C max In certain embodiments, administration of an MCT formulation that comprises substantially no protein and / or is administered in the substantial absence of protein can provide an immediate release (IR) of the MCT.

[0048] Certain embodiments of the present disclosure relate to administering MCT preparations in the substantial absence of protein-based drinks (e.g., Ensure and similar protein-based drinks and nutritional supplements). In other embodiments, MCT preparations may be administered in the substantial absence of protein-containing foods.

[0049] In certain embodiments, the subject has not substantially applied or consumed protein for about 30 minutes before the MCT preparation is applied. In other embodiments, the subject has not substantially applied or consumed protein for at least 30 minutes before the MCT preparation is applied. In other embodiments, the subject has not substantially applied or consumed protein for about 1 hour before the MCT preparation is applied. In other embodiments, the subject has not substantially applied or consumed protein for at least 1 hour before the MCT preparation is applied.

[0050] In certain embodiments, within 30 minutes after the MCT preparation is administered, the subject has substantially no application or consumption of protein. In other embodiments, at least 30 minutes after the MCT preparation is administered, the subject has substantially no application or consumption of protein. In other embodiments, within 1 hour after the MCT preparation is administered, the subject has substantially no application or consumption of protein. In other embodiments, at least 1 hour after the MCT preparation is administered, the subject has substantially no application or consumption of protein. In other embodiments, within 90 minutes after the MCT preparation is administered, the subject has substantially no application or consumption of protein. In other embodiments, at least 90 minutes after the MCT preparation is administered, the subject has substantially no application or consumption of protein. In other embodiments, within 2 hours after the MCT preparation is administered, the subject has substantially no application or consumption of protein. In other embodiments, at least 2 hours after the MCT preparation is administered, the subject has substantially no application or consumption of protein.

[0051] In certain embodiments, about 30 minutes before the MCT preparation is applied and about 30 minutes after the MCT preparation is applied, the subject does not substantially apply or consume protein. In other embodiments, at least 30 minutes before the MCT preparation is applied and at least 30 minutes after the MCT preparation is applied, the subject does not substantially apply or consume protein. In other embodiments, about 30 minutes before the MCT preparation is applied and about 1 hour after the MCT preparation is applied, the subject does not substantially apply or consume protein. In other embodiments, at least 30 minutes before the MCT preparation is applied and at least 1 hour after the MCT preparation is applied, the subject does not substantially apply or consume protein. In other embodiments, about 1 hour before the MCT preparation is applied and about 1 hour after the MCT preparation is applied, the subject does not substantially apply or consume protein. In other embodiments, at least 1 hour before the MCT preparation is applied and at least 1 hour after the MCT preparation is applied, the subject does not substantially apply or consume protein.

[0052] In one embodiment, the disclosed MCT preparations that are substantially free of protein and / or administered in the absence of substantially protein result in elevated ketone concentrations in the body. The MCT preparations can be administered in an amount effective to induce hyperketonemia. In one embodiment, hyperketonemia results in ketone bodies being used for energy in the brain.

[0053] In one embodiment, the disclosed MCT preparations that are substantially free of protein and / or administered in the absence of protein increase the circulating concentration of at least one type of ketone body in a subject. The amount of circulating ketone bodies can be measured multiple times after administration, and in one embodiment, the amount of circulating ketone bodies can be measured at a time predicted to be close to the peak concentration (C max ) time, but can also be measured before or after the predicted peak serum and / or plasma concentration level. The amounts measured at these off-peak times are then optionally adjusted to reflect the predicted levels at the predicted peak time. In one embodiment, the predicted peak serum and / or plasma concentration of at least one type of ketone body is at about 0.5 to about 3.0 hours. In another embodiment, the predicted peak serum and / or plasma concentration of at least one ketone body is at about 1.0 to about 2 hours. Peak serum and / or plasma concentrations and times can vary according to factors known to those skilled in the art, including individual digestion rates, co-ingestion or pre-ingestion or post-ingestion of food, beverages, etc., as known to those skilled in the art. Those skilled in the art will appreciate that other methods besides measuring serum and / or plasma levels can be used to determine ketone levels; for example, by measuring ketonuria excretion.

[0054] In one embodiment, the disclosed MCT preparations that are substantially free of protein and / or administered in the substantial absence of protein increase the circulating concentration of total ketone bodies in a subject. The disclosed MCT preparations that are substantially free of protein and / or administered in the substantial absence of protein can increase the concentration of total ketone bodies compared to MCT preparations that contain protein and / or are administered with protein.

[0055] In one embodiment, the disclosed MCT formulations that are substantially free of protein and / or administered in the substantial absence of protein can increase peak plasma concentrations of total ketone bodies (C max In one embodiment, the disclosed MCT formulations that are substantially free of protein and / or administered in the absence of protein can increase the peak serum concentration of total ketone bodies (C max ).

[0056] In one embodiment, the disclosed MCT formulations that are substantially free of protein and / or administered in the substantial absence of protein achieve a peak serum concentration of total ketone bodies (C max ) than the C of MCT preparations containing protein and / or administered with protein max In some embodiments, the peak serum concentration of total ketone bodies (C ) is about 10% greater, about 15% greater, about 20% greater, about 25% greater, about 30% greater, about 35% greater, about 40% greater, about 45% greater, about 50% greater, about 55% greater, about 60% greater, about 65% greater, about 70% greater, about 75% greater, about 80% greater, about 85% greater, about 90% greater, about 95% greater, or about 100% greater. In some embodiments, the peak serum concentration of total ketone bodies (C ) achieved by the disclosed MCT formulations that are substantially free of protein and / or administered in the absence of protein is about 10% greater, about 15% greater, about 20% greater, about 25% greater, about 30% greater, about 35% greater, about 40% greater, about 45% greater, about 50% greater, about 55% greater, about 60% greater, about 65% greater, about 70% greater, about 75% greater, about 80% greater, about 85% greater, about 90% greater, about 95% greater, or about 100% greater. max ) than the C of MCT preparations containing protein and / or administered with protein max At least 10% larger, at least 15% larger, at least 20% larger, at least 25% larger, at least 30% larger, at least 35% larger, at least 40% larger, at least 45% larger, at least 50% larger, at least 55% larger, at least 60% larger, at least 65% larger, at least 70% larger, at least 75% larger, at least 80% larger, at least 85% larger, at least 90% larger, at least 95% larger, or at least 100% larger.

[0057] In one embodiment, the peak serum concentration of total ketones (C max) is between about 350 micromoles / liter (μmol / L) and about 1000 μmol / L. In other embodiments, the peak serum concentration of total ketone bodies (C max ) is from about 350 to about 950 μmol / L, from about 350 to about 900 μmol / L, from about 350 to about 850 μmol / L, from about 350 to about 800 μmol / L, from about 350 to about 750 μmol / L, from about 350 to about 700 μmol / L, from about 350 to about 650 μmol / L, from about 350 to about 550 μmol / L, from about 350 to about 500 μmol / L, or from about 350 to about 800 μmol / L, although it will necessarily vary depending on the composition and the subject, for example, as discussed above. In other embodiments, the peak serum concentration of total ketone bodies (C max ) is from about 400 to about 950 μmol / L, from about 400 to about 900 μmol / L, from about 400 to about 850 μmol / L, from about 400 to about 800 μmol / L, from about 400 to about 750 μmol / L, from about 400 to about 700 μmol / L, from about 400 to about 650 μmol / L, from about 400 to about 600 μmol / L, or from about 400 to about 550 μmol / L. In certain embodiments, the peak serum concentration of total ketone bodies (C max ) is about 400 to about 600 μmol / L. In other embodiments, the peak serum concentration of total ketone bodies (C max ) is about 450 to about 550 μmol / L. In other embodiments, the peak serum concentration of total ketone bodies (C max ) is at least 350 μmol / L, at least 400 μmol / L, at least 450 μmol / L, at least 500 μmol / L at least 550 μmol / L or at least 600 μmol / L.

[0058] In one embodiment, the disclosed MCT preparations that are substantially free of protein and / or administered in the substantial absence of protein produce a C of total ketone bodies. max Time (T max ) are smaller than MCT preparations containing protein and / or administered with protein.

[0059] In one embodiment, the C of total ketone bodies achieved for a disclosed MCT preparation that is substantially free of protein and / or administered in the substantial absence of protein is max Time (T max) is about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours less than an MCT formulation that contains protein and / or is administered with protein. In certain embodiments, the C of total ketone bodies achieved for a disclosed MCT formulation that does not contain substantially protein and / or is administered in the substantial absence of protein is about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours less than an MCT formulation that contains protein and / or is administered with protein. max Time (T max ) is at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours less than an MCT preparation that contains protein and / or is administered with protein. In certain embodiments, the C of total ketone bodies achieved for a disclosed MCT preparation that does not contain substantially protein and / or is administered in the substantial absence of protein is at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours less than an MCT preparation that contains protein and / or is administered with protein. max Time (T max ) is at least 30 minutes less than an MCT formulation comprising and / or administered with protein.

[0060] In one embodiment, the C of total ketone bodies achieved for a disclosed MCT preparation that is substantially free of protein and / or administered in the substantial absence of protein is max Time (T max ) is about 0.5 hours to about 3 hours. In another embodiment, the total ketone bodies C max Time (T max ) is about 1 hour to about 2.5 hours. In another embodiment, the total ketone bodies C max Time (T max ) is about 1 hour to about 2 hours. In another embodiment, C max Time (T max ) is about 0.5 hours to about 1.5 hours. In another embodiment, the C of total ketone bodies is achieved. max Time (T max ) is about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours. In another embodiment, the C of total ketone bodies is achieved. max Time (T max ) is less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, or less than 1 hour. In certain embodiments, the C of total ketone bodies is achieved. max Time (T max ) is about 1 hour. In certain embodiments, the C of total ketone bodies is reached max Time (T max ) is about 1.5 hours. In certain embodiments, the C of total ketone bodies is reached max Time (T max ) is about 2 hours.

[0061] In certain embodiments, the disclosed MCT preparations that are substantially free of protein and / or administered in the substantial absence of protein increase the circulating concentration of at least one ketone body. In certain embodiments, the disclosed MCT preparations that are substantially free of protein and / or administered in the substantial absence of protein increase the circulating concentration of the ketone body beta-hydroxybutyrate (BHB). In certain embodiments, the disclosed MCT preparations that are substantially free of protein and / or administered in the substantial absence of protein increase the circulating concentration of the ketone body acetoacetate (AcAc). The disclosed MCT preparations that are substantially free of protein and / or administered in the substantial absence of protein can increase the concentration of at least one ketone body compared to MCT preparations that contain protein and / or are administered with protein.

[0062] In one embodiment, the disclosed MCT formulations that are substantially free of protein and / or administered in the substantial absence of protein can increase peak plasma concentrations (C ) of beta-hydroxybutyrate (BHB) compared to MCT formulations that are substantially free of protein and / or administered with protein. max In one embodiment, the disclosed MCT formulations that are substantially free of protein and / or administered in the absence of protein can increase the peak serum concentration (C ) of β-hydroxybutyrate (BHB) compared to MCT formulations that are substantially free of protein and / or administered with protein. max ).

[0063] In one embodiment, the disclosed MCT formulations that are substantially free of protein and / or administered in the substantial absence of protein achieve a peak serum concentration (C ) of β-hydroxybutyrate (BHB). max ) than the C of MCT preparations containing protein and / or administered with protein max In some embodiments, the peak serum concentration (C ) of β-hydroxybutyrate (BHB) achieved by the disclosed MCT formulations that are substantially free of protein and / or administered in the absence of protein is about 10% greater, about 15% greater, about 20% greater, about 25% greater, about 30% greater, about 35% greater, about 40% greater, about 45% greater, about 50% greater, about 55% greater, about 60% greater, about 65% greater, about 70% greater, about 75% greater, about 80% greater, about 85% greater, about 90% greater, about 95% greater, or about 100% greater. max ) than the C of MCT preparations containing protein and / or administered with protein maxAt least 10% larger, at least 15% larger, at least 20% larger, at least 25% larger, at least 30% larger, at least 35% larger, at least 40% larger, at least 45% larger, at least 50% larger, at least 55% larger, at least 60% larger, at least 65% larger, at least 70% larger, at least 75% larger, at least 80% larger, at least 85% larger, at least 90% larger, at least 95% larger, or at least 100% larger.

[0064] In one embodiment, the disclosed MCT formulations that are substantially free of protein and / or administered in the substantial absence of protein achieve a peak serum concentration (C ) of β-hydroxybutyrate (BHB). max ) is between about 350 micromoles / liter (μmol / L) and about 1000 μmol / L. In other embodiments, the peak serum concentration (C max ) is from about 350 to about 950 μmol / L, from about 350 to about 900 μmol / L, from about 350 to about 850 μmol / L, from about 350 to about 800 μmol / L, from about 350 to about 750 μmol / L, from about 350 to about 700 μmol / L, from about 350 to about 650 μmol / L, from about 350 to about 550 μmol / L, from about 350 to about 500 μmol / L, or from about 350 to about 800 μmol / L, although it will necessarily vary depending on the composition and the subject, for example, as discussed above. In other embodiments, the peak serum concentration (C max ) is from about 400 to about 950 μmol / L, from about 400 to about 900 μmol / L, from about 400 to about 850 μmol / L, from about 400 to about 800 μmol / L, from about 400 to about 750 μmol / L, from about 400 to about 700 μmol / L, from about 400 to about 650 μmol / L, from about 400 to about 600 μmol / L, or from about 400 to about 550 μmol / L. In certain embodiments, the peak serum concentration (C max ) is about 350 to about 600 μmol / L. In other embodiments, the peak serum concentration (C max ) is about 350 to about 550 μmol / L. In certain embodiments, the peak serum concentration (C max ) is about 400 to about 500 μmol / L. In other embodiments, the peak serum concentration (C max) is at least 350 μmol / L, at least 400 μmol / L, at least 450 μmol / L, at least 500 μmol / L at least 550 μmol / L or at least 600 μmol / L.

[0065] In one embodiment, the disclosed MCT formulations that are substantially free of protein and / or administered in the substantial absence of protein produce a C of β-hydroxybutyrate (BHB). max Time (T max ) are smaller than MCT preparations containing protein and / or administered with protein.

[0066] In one embodiment, the disclosed MCT preparations that contain substantially no protein and / or are administered in the substantial absence of protein have a C of β-hydroxybutyrate (BHB). max Time (T max ) is about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours less than an MCT formulation that contains protein and / or is administered with protein. In certain embodiments, the C of the disclosed MCT formulation that does not contain substantially protein and / or is administered in the absence of substantially protein to achieve β-hydroxybutyrate (BHB) is about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours less than an MCT formulation that contains protein and / or is administered with protein. max Time (T max ) is at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours less than an MCT formulation comprising protein and / or administered with protein. In certain embodiments, the C of the disclosed MCT formulations that do not substantially comprise protein and / or are administered in the substantial absence of protein to achieve β-hydroxybutyrate (BHB) is at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours less than an MCT formulation comprising protein and / or administered with protein. max Time (T max ) is at least 30 minutes less than an MCT formulation comprising and / or administered with protein.

[0067] In one embodiment, the disclosed MCT preparations that contain substantially no protein and / or are administered in the substantial absence of protein have a C of β-hydroxybutyrate (BHB). max Time (T max ) is about 0.5 hours to about 3 hours. In another embodiment, the C of β-hydroxybutyrate (BHB) is achieved. max Time (T max ) is about 1 hour to about 2.5 hours. In another embodiment, the C of β-hydroxybutyrate (BHB) is achieved. max Time (T max ) is about 1 hour to about 2 hours. In another embodiment, the C of β-hydroxybutyrate (BHB) is achieved. max Time (Tmax ) is about 0.5 hours to about 1.5 hours. In another embodiment, the C of β-hydroxybutyrate (BHB) is achieved. max Time (T max ) is about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours. In another embodiment, the C of β-hydroxybutyrate (BHB) is achieved. max Time (T max ) is less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, or less than 1 hour. In certain embodiments, the C of β-hydroxybutyrate (BHB) is achieved. max Time (T max ) is about 1 hour. In certain embodiments, the C of β-hydroxybutyrate (BHB) is achieved. max Time (T max ) is about 1.5 hours. In certain embodiments, the C of β-hydroxybutyrate (BHB) is achieved. max Time (T max ) is about 2 hours.

[0068] In one embodiment, the disclosed MCT formulations that are substantially free of protein and / or administered in the substantial absence of protein can increase the peak plasma concentration (C ) of acetoacetate (AcAc) compared to MCT formulations that are substantially free of protein and / or administered with protein. max In one embodiment, the disclosed MCT formulations that are substantially free of protein and / or administered in the absence of protein can increase the peak serum concentration (C ) of acetoacetate (AcAc) compared to MCT formulations that are substantially free of protein and / or administered with protein. max ).

[0069] In one embodiment, the disclosed MCT formulations that are substantially free of protein and / or administered in the substantial absence of protein achieve a peak serum concentration (C ) of acetoacetate (AcAc). max ) than the C of MCT preparations containing protein and / or administered with protein max In some embodiments, the peak serum concentration (C ) of acetoacetate (AcAc) achieved by the disclosed MCT formulations that are substantially free of protein and / or administered in the absence of protein is about 10% greater, about 15% greater, about 20% greater, about 25% greater, about 30% greater, about 35% greater, about 40% greater, about 45% greater, about 50% greater, about 55% greater, about 60% greater, about 65% greater, about 70% greater, about 75% greater, about 80% greater, about 85% greater, about 90% greater, about 95% greater, or about 100% greater. max) than the C of MCT preparations containing protein and / or administered with protein max At least 10% larger, at least 15% larger, at least 20% larger, at least 25% larger, at least 30% larger, at least 35% larger, at least 40% larger, at least 45% larger, at least 50% larger, at least 55% larger, at least 60% larger, at least 65% larger, at least 70% larger, at least 75% larger, at least 80% larger, at least 85% larger, at least 90% larger, at least 95% larger, or at least 100% larger.

[0070] In one embodiment, the disclosed MCT formulations that are substantially free of protein and / or administered in the substantial absence of protein achieve a peak serum concentration (C ) of acetoacetate (AcAc). max ) is between about 20 micromoles / liter (μmol / L) and about 200 μmol / L. In other embodiments, the peak serum concentration (C max ) is from about 20 to about 180 μmol / L, about 20 to about 160 μmol / L, about 20 to about 140 μmol / L, about 20 to about 120 μmol / L, about 20 to about 100 μmol / L, about 20 to about 80 μmol / L, about 20 to about 60 μmol / L, or about 20 to about 40 μmol / L, although it will necessarily vary depending on the composition and the subject, for example, as discussed above. In other embodiments, the peak serum concentration (C ) of acetoacetate (AcAc) is from about 20 to about 180 μmol / L, about 20 to about 160 μmol / L, about 20 to about 140 μmol / L, about 20 to about 120 μmol / L, about 20 to about 100 μmol / L, about 20 to about 80 μmol / L, about 20 to about 60 μmol / L, or about 20 to about 40 μmol / L. max ) is from about 40 to about 140 μmol / L, about 40 to about 100 μmol / L, or about 40 to about 80 μmol / L. In other embodiments, the peak serum concentration (C max ) is from about 60 to about 120 μmol / L. In other embodiments, the peak serum concentration (C max ) is at least 20 μmol / L, at least 30 μmol / L, at least 40 μmol / L, at least 50 μmol / L, at least 60 μmol / L, at least 70 μmol / L, at least 80 μmol / L, at least 90 μmol / L, at least 90 μmol / L, or at least 100 μmol / L. In other embodiments, the peak serum concentration (C max ) is at least 80 μmol / L.

[0071] In one embodiment, the disclosed MCT preparations that are substantially free of protein and / or administered in the substantial absence of protein produce a C of up to β-acetoacetate (AcAc). max Time (T max) are smaller than MCT preparations containing protein and / or administered with protein.

[0072] In one embodiment, the disclosed MCT preparations that are substantially free of protein and / or administered in the substantial absence of protein have a C of acetoacetate (AcAc). max Time (T max ) is about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours less than an MCT formulation comprising and / or administered with protein. In certain embodiments, the C of acetoacetate (AcAc) to which the disclosed MCT formulations that do not substantially comprise protein and / or are administered in the substantial absence of protein is less than about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours less than an MCT formulation comprising and / or administered with protein. max Time (T max ) is at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours less than an MCT preparation that contains protein and / or is administered with protein. In certain embodiments, the C of acetoacetate (AcAc) to which the disclosed MCT preparations that do not contain substantially protein and / or are administered in the substantial absence of protein is less than 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours less than an MCT preparation that contains protein and / or is administered with protein. max Time (T max ) is at least 30 minutes less than an MCT formulation comprising and / or administered with protein.

[0073] In one embodiment, the disclosed MCT preparations that are substantially free of protein and / or administered in the substantial absence of protein have a C of acetoacetate (AcAc). max Time (T max ) is about 0.5 hours to about 3 hours. In another embodiment, the C of acetoacetic acid (AcAc) is reached. max Time (T max ) is about 1 hour to about 2.5 hours. In another embodiment, the C of acetoacetic acid (AcAc) is reached. max Time (T max ) is about 1 hour to about 2 hours. In another embodiment, the C of acetoacetic acid (AcAc) is reached. max Time (T max ) is about 0.5 hours to about 1.5 hours. In another embodiment, the C of acetoacetic acid (AcAc) is reached. max Time (T max ) is about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours or about 3 hours. In another embodiment, the C of acetoacetate (AcAc) is reached. max Time (T max) is less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, or less than 1 hour. In certain embodiments, the C of acetoacetate (AcAc) is achieved. max Time (T max ) is about 1 hour. In certain embodiments, the C of acetoacetate (AcAc) is reached. max Time (T max ) is about 1.5 hours. In certain embodiments, the C of acetoacetate (AcAc) is reached. max Time (T max ) is about 2 hours.

[0074] In other embodiments of the present disclosure, MCT preparations comprising and / or administered with proteins can provide a slower release of MCT. In certain embodiments, the administration of MCT preparations comprising and / or administered with low protein / no protein can provide sustained release (SR), delayed release (DR) and / or controlled release (CR) of MCT.

[0075] Those skilled in the art will appreciate that the amount of protein administered with and / or present in the MCT formulation can be varied to achieve the desired release characteristics of the MCT. For example, a lower amount of protein can provide a faster sustained / delayed / controlled release than a higher amount of protein.

[0076] In certain embodiments, in parallel with the use of MCT preparations, the subject uses or consumes protein. In other embodiments, while the MCT preparation is used, the subject uses or consumes protein. In certain embodiments, less than 30 minutes before the MCT preparation is used, the subject uses or consumes protein. In other embodiments, less than 30 minutes after the MCT preparation is used, the subject uses or consumes protein. In certain embodiments, less than 30 minutes before the MCT preparation is used and less than 30 minutes after the MCT preparation is used, the subject uses or consumes protein. In certain embodiments, 15 minutes or less before the MCT preparation is used, the subject uses or consumes protein. In other embodiments, 15 minutes or less after the MCT preparation is used, the subject uses or consumes protein. In certain embodiments, 15 minutes or less before the MCT preparation is used and 15 minutes or less after the MCT preparation is used, the subject uses or consumes protein.

[0077] In one embodiment, the disclosed MCT preparations comprising and / or administered with a protein result in elevated ketone concentrations in the body that are less than the ketone concentrations of an MCT preparation that does not substantially comprise and / or is administered in the absence of substantially any protein. The MCT preparation can be administered in an amount effective to induce hyperketonemia. In one embodiment, hyperketonemia results in ketone bodies being used for energy in the brain.

[0078] The disclosed MCT preparations comprising and / or administered with protein can have a lower total ketone body concentration compared to MCT preparations comprising substantially no protein and / or administered in the substantial absence of protein.

[0079] In one embodiment, the disclosed MCT formulations comprising and / or administered with a protein can reduce the peak plasma concentration of total ketone bodies (C 100,000,000) compared to an MCT formulation that does not substantially comprise a protein and / or is administered in the substantial absence of a protein. max In one embodiment, the disclosed MCT formulations comprising and / or administered with a protein can reduce the peak serum concentration of total ketone bodies (C ) compared to an MCT formulation that does not substantially comprise the protein and / or is administered in the presence of substantially no protein. max ).

[0080] In one embodiment, the disclosed MCT formulations comprising and / or administered with a protein achieve a peak serum concentration of total ketone bodies (C max ) than the C of an MCT preparation that contains substantially no protein and / or is administered in the absence of substantially protein. max In some embodiments, the peak serum concentration of total ketone bodies (C ) achieved by the disclosed MCT formulations comprising and / or administered with a protein is about 10% lower, about 15% lower, about 20% lower, about 25% lower, about 30% lower, about 35% lower, about 40% lower, about 45% lower, about 50% lower, about 55% lower, about 60% lower, about 65% lower, about 70% lower, about 75% lower, about 80% lower, about 85% lower, about 90% lower, about 95% lower, or about 100% lower. max ) than the C of an MCT preparation that contains substantially no protein and / or is administered in the absence of substantially protein. max At least 10% lower, at least 15% lower, at least 20% lower, at least 25% lower, at least 30% lower, at least 35% lower, at least 40% lower, at least 45% lower, at least 50% lower, at least 55% lower, at least 60% lower, at least 65% lower, at least 70% lower, at least 75% lower, at least 80% lower, at least 85% lower, at least 90% lower, at least 95% lower, or at least 100% lower.

[0081] In one embodiment, the disclosed MCT formulations comprising and / or administered with protein result in a C of total ketones of max Time (T max ) is greater than an MCT preparation that contains substantially no protein and / or is administered in the absence of substantially protein.

[0082] In one embodiment, the disclosed MCT preparations comprising protein and / or administered with protein achieve a C of total ketone bodies. max Time (T max ) is about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours greater than an MCT formulation that does not substantially comprise protein and / or is administered in the absence of protein. In certain embodiments, the C of total ketone bodies achieved in a disclosed MCT formulation comprising protein and / or administered with protein is about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours greater than an MCT formulation that does substantially comprise protein and / or is administered in the absence of protein. max Time (T max ) is at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours greater than an MCT formulation that does not substantially comprise protein and / or is administered in the absence of protein. In certain embodiments, the C of total ketone bodies achieved in a disclosed MCT formulation comprising protein and / or administered with protein is at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours greater than an MCT formulation that does substantially comprise protein and / or is administered in the absence of protein. max Time (T max ) is at least 60 minutes greater than an MCT formulation comprising substantially no protein and / or administered in the absence of substantially protein.

[0083] In certain embodiments, the disclosed MCT preparations comprising proteins and / or administered with proteins increase the circulating concentration of at least one ketone body. In certain embodiments, the disclosed MCT preparations comprising proteins and / or administered with proteins increase the circulating concentration of the ketone body beta-hydroxybutyrate (BHB). In certain embodiments, the disclosed MCT preparations comprising proteins and / or administered with proteins increase the circulating concentration of the ketone body acetoacetate (AcAc). Compared to MCT preparations that are substantially free of proteins and / or administered in the absence of substantially any proteins, the disclosed MCT preparations comprising proteins and / or administered with proteins can reduce the concentration of at least one ketone body.

[0084] In one embodiment, the disclosed MCT formulations comprising and / or administered with a protein can reduce the peak plasma concentration (C ) of beta-hydroxybutyrate (BHB) compared to an MCT formulation that does not substantially comprise protein and / or is administered in the substantial absence of protein. max In one embodiment, the disclosed MCT formulations comprising and / or administered with a protein can reduce the peak serum concentration (C ) of β-hydroxybutyrate (BHB) compared to an MCT formulation that does not substantially comprise the protein and / or is administered in the presence of substantially no protein. max ).

[0085] In one embodiment, the disclosed MCT formulations comprising and / or administered with a protein achieve a peak serum concentration (Cmax ) than the C of an MCT preparation that contains substantially no protein and / or is administered in the absence of substantially protein. max In some embodiments, the peak serum concentration (C ) of β-hydroxybutyrate (BHB) achieved by the disclosed MCT formulations comprising and / or administered with a protein is about 10% lower, about 15% lower, about 20% lower, about 25% lower, about 30% lower, about 35% lower, about 40% lower, about 45% lower, about 50% lower, about 55% lower, about 60% lower, about 65% lower, about 70% lower, about 75% lower, about 80% lower, about 85% lower, about 90% lower, about 95% lower, or about 100% lower. max ) than the C of an MCT preparation that contains substantially no protein and / or is administered in the absence of substantially protein. max At least 10% lower, at least 15% lower, at least 20% lower, at least 25% lower, at least 30% lower, at least 35% lower, at least 40% lower, at least 45% lower, at least 50% lower, at least 55% lower, at least 60% lower, at least 65% lower, at least 70% lower, at least 75% lower, at least 80% lower, at least 85% lower, at least 90% lower, at least 95% lower, or at least 100% lower.

[0086] In one embodiment, the disclosed MCT formulations comprising and / or administered with a protein result in achieving a C of β-hydroxybutyrate (BHB). max Time (T max ) is greater than an MCT preparation that contains substantially no protein and / or is administered in the absence of substantially protein.

[0087] In one embodiment, the disclosed MCT formulations comprising protein and / or administered with protein achieve a C of β-hydroxybutyrate (BHB). max Time (T max ) is about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours greater than an MCT formulation that does not substantially contain protein and / or is administered in the absence of protein. In certain embodiments, the C of total ketone bodies achieved in a disclosed MCT formulation that contains protein and / or is administered with protein is about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours greater than an MCT formulation that does substantially contain protein and / or is administered in the absence of protein. max Time (T max ) is at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours greater than an MCT formulation that does not substantially comprise protein and / or is administered in the absence of protein. In certain embodiments, the C of total ketone bodies achieved in a disclosed MCT formulation comprising protein and / or administered with protein is at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours greater than an MCT formulation that does substantially comprise protein and / or is administered in the absence of protein.max Time (T max ) is at least 60 minutes greater than an MCT formulation comprising substantially no protein and / or administered in the absence of substantially protein.

[0088] In one embodiment, the disclosed MCT formulations comprising and / or administered with a protein can reduce the peak plasma concentration (C ) of acetoacetate (AcAc) compared to an MCT formulation that does not substantially comprise the protein and / or is administered in the substantial absence of the protein. max In one embodiment, the disclosed MCT formulations comprising and / or administered with a protein can reduce the peak serum concentration (C ) of acetoacetate (AcAc) compared to an MCT formulation that does not substantially comprise the protein and / or is administered in the presence of substantially no protein. max ).

[0089] In one embodiment, the disclosed MCT formulations comprising and / or administered with a protein achieve a peak serum concentration (C ) of acetoacetate (AcAc). max ) than the C of an MCT preparation that contains substantially no protein and / or is administered in the absence of substantially protein. max In some embodiments, the peak serum concentration (C ) of acetoacetate (AcAc) achieved by the disclosed MCT formulations comprising and / or administered with a protein is about 10% lower, about 15% lower, about 20% lower, about 25% lower, about 30% lower, about 35% lower, about 40% lower, about 45% lower, about 50% lower, about 55% lower, about 60% lower, about 65% lower, about 70% lower, about 75% lower, about 80% lower, about 85% lower, about 90% lower, about 95% lower, or about 100% lower. max ) than the C of an MCT preparation that contains substantially no protein and / or is administered in the absence of substantially protein. max At least 10% lower, at least 15% lower, at least 20% lower, at least 25% lower, at least 30% lower, at least 35% lower, at least 40% lower, at least 45% lower, at least 50% lower, at least 55% lower, at least 60% lower, at least 65% lower, at least 70% lower, at least 75% lower, at least 80% lower, at least 85% lower, at least 90% lower, at least 95% lower, or at least 100% lower.

[0090] In one embodiment, the disclosed MCT formulations comprising and / or administered with a protein result in a C of β-acetoacetate (AcAc). max Time (T max ) is greater than an MCT preparation that contains substantially no protein and / or is administered in the absence of substantially protein.

[0091] In one embodiment, the disclosed MCT preparations comprising and / or administered with a protein have a C of acetoacetate (AcAc). max Time (T max ) is about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours greater than an MCT formulation that does not substantially contain protein and / or is administered in the absence of protein. In certain embodiments, the C of total ketone bodies achieved in a disclosed MCT formulation that contains protein and / or is administered with protein is about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours greater than an MCT formulation that does substantially contain protein and / or is administered in the absence of protein. max Time (T max ) is at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours greater than an MCT formulation that does not substantially comprise protein and / or is administered in the absence of protein. In certain embodiments, the C of total ketone bodies achieved in a disclosed MCT formulation comprising protein and / or administered with protein is at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours greater than an MCT formulation that does substantially comprise protein and / or is administered in the absence of protein. max Time (T max ) is at least 60 minutes greater than an MCT formulation comprising substantially no protein and / or administered in the absence of substantially protein.

[0092] Those skilled in the art will appreciate that in certain cases, the analysis of ketone body measurement / quantification may be adjusted to account for errors, baseline measurements, etc. The amount of one or more ketone bodies may be determined from whole blood, plasma, serum, and / or combinations thereof. The amount of one or more ketone bodies may be determined by methods known to those skilled in the art, including, but not limited to, enzymatic assays and liquid chromatography-tandem mass spectrometry (LC-MS).

[0093] In other embodiments of the present disclosure, MCT preparations comprising a combination of components, one component having low protein / no protein and one component having protein, can provide: combined IR and SR / DR / CR pharmacokinetic properties, wherein the protein-based component provides an IR phase and the low protein / no protein component provides an SR / DR / CR phase.

[0094] In certain embodiments, the MCT preparation may include at least two components—a first component that allows IR pharmacokinetic properties and a second component that allows SR / DR / CR pharmacokinetic properties. Each component may include a therapeutically effective amount of MCT. The amount of MCT in each component can be easily determined by one skilled in the art based on the desired results and pharmacokinetic properties and the disease / disorder to be treated and the characteristics of the intended subject or subject population.

[0095] In one embodiment, the first component (IR) may be substantially free of protein and the second component (SR / DR / CR) may contain protein. In order to maintain the IR pharmacokinetic properties, the MCT preparation may be administered substantially without protein. In certain embodiments, about 30 minutes before the MCT preparation is administered, the subject does not substantially administer or consume protein. In other embodiments, at least 30 minutes before the MCT preparation is administered, the subject does not substantially administer or consume protein. In other embodiments, about 1 hour before the MCT preparation is administered, the subject does not substantially administer or consume protein. In other embodiments, at least 1 hour before the MCT preparation is administered, the subject does not substantially administer or consume protein. In certain embodiments, within 30 minutes after the MCT preparation is administered, the subject does not substantially administer or consume protein. In other embodiments, at least 30 minutes after the MCT preparation is administered, the subject does not substantially administer or consume protein. In other embodiments, within 1 hour after the MCT preparation is administered, the subject does not substantially administer or consume protein. In other embodiments, at least 1 hour after the MCT preparation is administered, the subject does not substantially administer or consume protein. In other embodiments, the subject does not substantially administer or consume protein within 90 minutes after administration of the MCT formulation. In other embodiments, the subject does not substantially administer or consume protein for at least 90 minutes after administration of the MCT formulation.

[0096] In one embodiment, the second component (SR / DR / CR) may contain protein. The second component (SR / DR / CR) may be formulated so that it does not interfere with the immediate release of the first component (IR). In certain embodiments, the first component (IR) comprises a therapeutically effective amount of the first portion of MCT, which is substantially released within 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours after the MCT preparation is administered. In one embodiment, the first component comprises a therapeutically effective amount of the first portion of MCT, which is substantially released within 1 hour after the MCT preparation is administered. In one embodiment, the first component comprises a therapeutically effective amount of the first portion of MCT, which is substantially released within 2 hours after the MCT preparation is administered. In one embodiment, the first component comprises a therapeutically effective amount of the first portion of MCT, which is substantially released within 3 hours after the MCT preparation is administered. In certain embodiments, the second component (SR / DR / CR) comprises a therapeutically effective amount of the second portion of MCT, which is substantially released after the MCT preparation is administered for 2 or more hours, 2.5 or more hours, 3 hours or more hours, 3.5 or more hours, 4.0 or more hours, 4.5 or more hours, or 5 or more hours. In one embodiment, the first component comprises a therapeutically effective amount of a second portion of MCT that is substantially released over 2 or more hours. In one embodiment, the second component comprises a therapeutically effective amount of a second portion of MCT that is substantially released over 3 or more hours. In one embodiment, the second component comprises a therapeutically effective amount of a first portion of MCT that is substantially released over 4 or more hours.

[0097] In certain embodiments, the first component (IR) can be administered to a subject separately from the second component (SR / DR / CR). Thus, another aspect of the present disclosure is a method of administering a first component (IR) comprising MCT substantially in the absence of protein, and then administering a second component (SR / DR / CR) comprising MCT and protein. In another embodiment, a method of administering a first component (IR) comprising MCT substantially in the absence of protein, and then administering a second component (SR / DR / CR) comprising MCT together with protein is disclosed. In one embodiment, the first and second components can be administered at intervals of about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours. In one embodiment, the first and second components can be administered at intervals of at least 30 minutes, at least 45 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours.

[0098] In another embodiment, the second component is applied at least several minutes after the first component and is applied together with the protein. The second component may comprise the protein, or the protein may be applied together with the second component. When the protein is applied together with the second component, it may be applied within at least 15 minutes, at least 30 minutes, at least 45 minutes or at least 60 minutes of the second component.

[0099] The present disclosure further generally relates to pharmaceutical compositions comprising high-load active agents, the active agents comprising at least one MCT, and methods of preparing and using such compositions. As discussed, in certain embodiments, the MCT preparations are substantially free of protein. In other embodiments, the MCT preparations may contain protein.

[0100] In one embodiment, it was unexpectedly discovered that improved bioavailability of MCT and in vivo formation of active metabolites, ketone bodies, can be achieved by MCT formulations that form stable emulsions of high drug load MCT in the presence and absence of protein.

[0101] In certain aspects, the MCT formulations of the present disclosure form stable emulsions when reconstituted in an aqueous environment of use, such as in water or when administered in vivo.

[0102] In certain embodiments, the emulsion formed does not phase separate during the stability period. As an example, the emulsion can be stable for at least about 10 minutes, at least about 20 minutes, at least about 30 minutes, at least about 45 minutes, at least about 1 hour, at least about 2 hours, at least about 4 hours, at least about 5 hours, at least about 24 hours, etc.

[0103] In certain aspects, emulsions are generally stable under ambient conditions and neutral pH, as well as under physiological conditions following administration (eg, under body temperature and physiological pH conditions in the stomach).

[0104] In certain embodiments, the emulsion formed can be stable at stomach pH, ​​for example, at a pH of about 1 to about 3, about 1.2-2.9, etc. In certain embodiments, the emulsion formed can be stable at intestinal and / or colonic pH, for example, at a pH of about 5 to about 7, about 5.5 to about 6.9, etc. In certain embodiments, the emulsion formed can begin to decompose or phase separate at stomach pH after about 1 / 2 to about 1 hour, but will not release the encapsulated MCT before intestinal or colonic pH. In this regard, it is not intended to be limited by theory, and in vitro digestion assays indicate that the encapsulated MCT is released from the emulsion at intestinal and / or colonic pH, which is the main location of lipid digestive enzymes. According to certain aspects of the present disclosure, the preferential release of MCT in the intestine and / or colon rather than in the stomach can increase the bioavailability of MCT, considering the positioning of lipid digestive enzymes in these areas.

[0105] In certain embodiments, the formed emulsion may begin to break down or phase separate after about 0.5 to about 1 hour at gastric pH, but will not release the absorbed / encapsulated or otherwise included high drug load MCT until intestinal or colonic pH.

[0106] In this regard, certain aspects of the present disclosure relate to preferential release of high drug load MCT in the intestine and / or colon rather than in the stomach. Without intending to be limited by theory, given that the colon is the primary location for lipid digestive enzymes compared to the stomach, such preferential release in the intestine and / or colon can increase the bioavailability of MCT.

[0107] In some aspects, MCT preparations produce stable emulsions with small average droplet particle size. Small average droplet particle size produces large relative surface area of ​​emulsion droplets in emulsion. Not intended to be limited by theory, this large relative surface area of ​​emulsion droplets provides large surface area for lipid digestion enzymes to release adsorbed / encapsulated or otherwise incorporated MCT, and thereby MCT is decomposed into active metabolite ketone bodies. In this way, the larger the relative surface area of ​​emulsion droplets, the larger the amount of MCT that can be used for lipid digestion enzymes, and the larger the amount of active metabolite ketone bodies produced. In certain embodiments, the average droplet diameter of the emulsion may be less than about 1000nm, but greater than about 100nm, for example, between about 100nm and 500nm, between about 200nm and about 300nm, etc.

[0108] In other aspects of the present disclosure, and again without intending to be limited by theory, preferential release of MCTs in the colon can provide reduced gastric discomfort and related adverse events compared to standard administration of non-formulated MCT oil.

[0109] In other aspects of the disclosure, as described above, improved bioavailability of MCTs can generally result in increased production of active metabolites, ketone bodies, in vivo compared to standard administration of non-formulated MCT oil or compared to administration of MCTs formulated with and / or administered with protein.

[0110] In summary, a stable emulsion of MCT containing small emulsion droplets will provide good bioavailability of MCT, in part because the high surface area emulsion droplets facilitate efficient digestion of MCT into active metabolites, ketone bodies, by lipid digesting enzymes in the colon. Without being limited by theory, MCT formulations containing or administered with proteins coagulate at gastric pH, causing the formulation to break down the emulsion and release the API into the stomach. Such formulations are generally less used for colonic lipid digesting enzymes, and therefore the bioavailability of MCT is lower.

[0111] MCT formulations comprising and / or administered with low / no protein and forming stable emulsions under environmental and physiological conditions (including gastric pH) provide: higher bioavailability, lower dose volume, and reduced AEs compared to protein-based MCT formulations, thus, a reduced patient titration period.

[0112] In certain embodiments, the pharmaceutical composition may include a high drug load active agent comprising or consisting essentially of at least one MCT (such as caprylic triglyceride) in an amount of at least about 30% by weight of the total composition, at least about 35% by weight of the total composition, at least about 40% by weight of the total composition, from about 30% by weight of the total composition to about 65% by weight of the total composition, from about 30% by weight of the total composition to about 60% by weight of the total composition, from about 35% by weight of the total composition to about 60% by weight of the total composition, from about 40% by weight of the total composition to about 55% by weight of the total composition, from about 40% by weight of the total composition to about 50% by weight of the total composition, etc.

[0113] As used herein, "weight %" means "weight % of the total composition" unless otherwise indicated.

[0114] In certain aspects, the solid pharmaceutical composition of the present disclosure may comprise a high drug load active agent, at least one or two surfactants, an adsorbent, and a film-forming polymer, wherein the active agent comprises or consists essentially of at least one MCT. The pharmaceutical composition may also include a co-surfactant.

[0115] In certain aspects of the present disclosure, MCT refers to any glycerol molecule ester-linked to three fatty acid molecules, each fatty acid molecule having a carbon chain of 5-12 carbons. In certain embodiments, the pharmaceutical composition may include MCT represented by the following general formula:

[0116]

[0117] Wherein R1, R2 and R3 are fatty acids having 5-12 carbons in the carbon backbone esterified to the glycerol backbone.

[0118] The MCT of the present disclosure can be prepared by any method known in the art, such as direct esterification, rearrangement, fractionation, transesterification, etc. The source of MCT includes any suitable source, semi-synthetic, synthetic or natural. Examples of natural sources of MCT include plant sources, such as coconuts and coconut oil, palm kernels and palm kernel oil; and animal sources, such as milk from any of a number of species (e.g., goats). For example, lipids can be prepared by rearrangement of vegetable oils (e.g., coconut oil). The length and distribution of chain lengths may vary depending on the source oil. For example, MCTs containing 1-10% C6, 30-60% C8, 30-60% C10, 1-10% C10 are typically derived from palm oil and coconut oil.

[0119] According to certain embodiments of the present disclosure, a solid pharmaceutical composition of the present disclosure may comprise an active agent comprising or consisting essentially of an MCT having greater than about 95% (e.g., 98%) C8 at R1, R2, and R3 and referred to herein as caprylic triglyceride ("CT").

[0120] In certain embodiments, the MCT is caprylic triglyceride, as described herein. Exemplary sources of CT include MIGLYOL 808 or NEOBEE 895. In certain aspects, CT can be obtained from coconut or palm kernel oil, prepared by, for example, semi-synthetic esterification of octanoic acid with glycerol.

[0121] In other embodiments, the solid pharmaceutical composition may include an active agent comprising or consisting essentially of MCT wherein R1, R2, and R3 are fatty acids containing a six-carbon backbone (tri-C6:0). In many animal model systems, tri-C6:0 MCT is very rapidly absorbed by the gastrointestinal tract. The high absorption rate results in rapid perfusion of the liver and an effective ketogenic response. In another embodiment, the pharmaceutical composition may include an active agent comprising or consisting essentially of MCT wherein R1, R2, and R3 are fatty acids containing an eight-carbon backbone (tri-C8:0). In another embodiment, the pharmaceutical composition may include an active agent comprising or consisting essentially of MCT wherein R1, R2, and R3 are fatty acids containing a ten-carbon backbone (tri-C10:0). In another embodiment, the pharmaceutical composition may include MCT wherein R1, R2, and R3 are a mixture of C8:0 and C10:0 fatty acids. In another embodiment, the pharmaceutical composition may include an active agent comprising or consisting essentially of an MCT wherein R1, R2, and R3 are a mixture of C6:0, C8:0, C10:0, and C12:0 fatty acids. In another embodiment, the pharmaceutical composition may include an active agent comprising or consisting essentially of an MCT wherein greater than 95% of R1, R2, and R3 are 8 carbons in length. In another embodiment, the pharmaceutical composition may include an active agent comprising or consisting essentially of an MCT wherein R1, R2, and R3 carbon chains are 6-carbon or 10-carbon chains. In another embodiment, the pharmaceutical composition may include an active agent comprising or consisting essentially of an MCT wherein about 50% of R1, R2, and R3 are 8 carbons in length and about 50% of R1, R2, and R3 are 10 carbons in length. In one embodiment, the pharmaceutical composition may comprise an active agent comprising or consisting essentially of MCT wherein R1, R2 and R3 are 6, 7, 8, 9, 10 or 12 carbon chain lengths or mixtures thereof.

[0122] As discussed, in certain embodiments of the present disclosure, MCT formulations are contemplated that include at least two components containing MCTs—at least one component that allows for IR pharmacokinetic properties, and at least one component that allows for SR / DR / CR pharmacokinetic properties. It will be appreciated by those skilled in the art that a multi-component MCT formulation can be determined in light of the present disclosure.

[0123] In certain aspects, the present disclosure relates to a method of treating a disease or disorder associated with decreased cognitive function in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of the present disclosure in an amount effective to increase the concentration of ketone bodies in the subject, thereby treating the disease or disorder. In certain embodiments, the pharmaceutical composition of the present disclosure can be administered outside the context of a ketogenic diet. For example, in the context of the present disclosure, carbohydrates can be consumed simultaneously with the pharmaceutical compositions disclosed herein.

[0124] According to certain aspects of the present disclosure, the diseases and disorders associated with cognitive decline include: age-associated memory impairment (AAMI), Alzheimer's disease (AD), Parkinson's disease, Friedreich's ataxia (FRDA), GLUT1-deficient epilepsy, leprechaun syndrome and Rabson-Mendenhall syndrome, coronary artery bypass graft (CABG) dementia, anesthesia-induced memory loss, Huntington's disease and many others.

[0125] In another embodiment, the patient suffers from or is at risk for disease-associated cognitive decline caused by decreased neuronal metabolism, such as, for example, cognitive decline associated with Alzheimer's disease (AD), Parkinson's disease, Friedreich's ataxia (FRDA), GLUT1-deficient epilepsy, leprechaun syndrome and Rabson-Mendenhall syndrome, coronary artery bypass graft (CABG) dementia, anesthesia-induced memory loss, Huntington's disease and many others.

[0126] In another embodiment, the subject lacks the ApoE4 genotype described in US Pat. No. 8,445,535, which is hereby incorporated by reference in its entirety.

[0127] As used herein, reduced neuronal metabolism means all possible mechanisms that may lead to reduced neuronal metabolism. Such mechanisms include, but are not limited to, mitochondrial dysfunction, free radical attack, generation of reactive oxygen species (ROS), ROS-induced neuronal apoptosis, poor glucose transport or glycolysis, membrane ion potential imbalance, calcium flux dysfunction, etc.

[0128] According to the present invention, high blood ketone levels will provide an energy source for brain cells with impaired glucose metabolism, thereby leading to improved performance of cognitive functions. As used herein, "subject" and "patient" are used interchangeably and refer to any mammal, including humans, that may benefit from treatment of diseases and disorders associated with or caused by reduced neuronal metabolism.

[0129] "Effective amount" means the amount of a compound, material or pharmaceutical composition as described herein that effectively achieves a specific biological result. The effectiveness of treating the above-mentioned disease can be assessed by the improved results from at least one neuropsychological test. These neuropsychological tests are known in the art and include the Global Impression of Clinical Change (CGIC), the Leibniz Auditory Verbal Learning Test (RAVLT), the Name Association Test (FLN), the Telephone Dial Test (TDT), the Memory Assessment Clinic Self-rating Scale (MAC-S), the Symbol Digital Coding (SDC), the SDC Delayed Recall Task (DRT), the Divided Attention Test (DAT), the Visual Serial Comparison (VSC), the DAT Dual Task (DAT Dual), the Brief Mental State Examination (MMSE) and the Geriatric Depression Scale (GDS) etc.

[0130] The term "cognitive function" refers to a special, normal or appropriate physiological activity of the brain, including, but not limited to, at least one of the following: mental stability, memory / recall ability, problem-solving ability, reasoning ability, thinking ability, judgment ability, learning ability, perception, intuition, attention and consciousness. "Enhanced cognitive function" or "improved cognitive function" refers to a special, normal or appropriate physiological activity of the brain, including, but not limited to, any improvement in at least one of the following: mental stability, memory / recall ability, problem-solving ability, reasoning ability, thinking ability, judgment ability, learning ability, perception, intuition, attention and consciousness, which can be measured by any suitable method in the art. "Decline in cognitive function" or "impaired cognitive function" refers to any decrease in a special, normal or appropriate physiological activity of the brain.

[0131] In another embodiment, the method of the present invention further comprises determining the patient's genotype or specific allele. In one embodiment, the patient's apolipoprotein E gene allele is determined. It has been found that when ketone body levels are induced to increase with MCT, non-E4 carriers perform better than carriers with the E4 allele. Moreover, those with the E4 allele have higher fasting ketone body levels, and the levels continue to rise over a two-hour time interval. Therefore, E4 carriers may need higher ketone levels or agents that increase the ability to use existing ketone bodies.

[0132] In one embodiment, the pharmaceutical compositions of the present disclosure are administered orally. The therapeutically effective amount of the therapeutic agent can be any amount or dosage sufficient to produce the desired effect, and depends in part on the severity and stage of the condition, the size and condition of the patient, and other factors known to those skilled in the art. As discussed elsewhere herein, the dosage can be administered in a single dose or in several doses, e.g., in divided doses over the course of several weeks.

[0133] In one embodiment, the pharmaceutical compositions of the present disclosure are administered at a specific dose required to increase blood ketone bodies to the level required to treat and / or prevent the occurrence of any disease-related or age-related cognitive decline, such as AD, AAMI, etc. Appropriate doses can be determined by one skilled in the art.

[0134] In one embodiment, oral administration of a pharmaceutical composition of the present disclosure results in hyperketonemia. In one embodiment, hyperketonemia results in ketone bodies being used for energy in the brain even in the presence of glucose. In addition, hyperketonemia results in a significant (39%) increase in cerebral blood flow (Hasselbalch, SG, et al., Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia, Am J Physiol, 1996, 270: E746-51). Hyperketonemia is reported to reduce cognitive dysfunction associated with systemic hypoglycemia in normal humans (Veneman, T., et al., Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans, Diabetes, 1994, 43: 1311-7). Please note that systemic hypoglycemia is different from local defects in glucose metabolism that occur in any disease-related or age-related cognitive decline (such as AD, AAMI, etc.).

[0135] For example, it can be administered once a month, once a week, once a day, or multiple times a day on a basis as needed or desired. Similarly, administration can be every other day, a week, or a month, every three days, a week, or a month, every four days, a week, or a month, etc. Administration can be multiple times a day. When used as a supplement for common dietary requirements, the composition can be administered directly to the patient, or otherwise contacted or mixed with daily feeding or food.

[0136] In one embodiment, the pharmaceutical compositions provided herein are intended for "long-term" consumption, sometimes referred to herein as "extended" phases. "Long-term" administration as used herein generally refers to a phase of more than one month. Phases of more than two, three or four months constitute an embodiment of the present invention. Also included are embodiments comprising a more extended phase, which include more than 5, 6, 7, 8, 9 or 10 months. Also included are phases of more than 11 months or 1 year. Longer-term use of more than 1, 2, 3 or more years is also contemplated herein. "Regularly" as used herein refers to administration of a composition or consumption of a composition at least once a week. Including more frequent administration or consumption, for example twice or three times a week. Also included are schemes comprising at least one consumption per day. A skilled technician will appreciate that the blood levels of ketone bodies or specific ketone bodies achieved may be a valuable measure of the frequency of administration. Any frequency (whether or not explicitly exemplified herein) that allows the blood levels of the measured compound to be maintained within an acceptable range may be considered useful herein. The skilled artisan will appreciate that the frequency of administration varies with the composition consumed or administered, and that some compositions may require more or less frequent administration to maintain a desired blood level of the compound being measured (eg, ketone bodies).

[0137] Can be used regularly, for example, as a part of the treatment regimen in the patient.The treatment regimen can comprise and make the patient regularly take in the pharmaceutical composition of the present disclosure with the amount that effectively enhances the patient's cognitive function, memory and behavior.Regular intake can be once a day, or twice a day, three times, four times or more times, carried out on a daily or weekly basis.Similarly, regular use can be every other day or week, every three days or week, every four days or week, every five days or week, or every six days or week, and in this scheme, use can be every day repeatedly.As illustrated in this article, the target of regular use is, to provide the pharmaceutical composition of the present disclosure of optimal dose to the patient.

[0138] Doses of compositions of the invention (e.g., compositions comprising MCTs) can be administered in amounts effective to increase cognitive abilities in patients with diseases in which neuronal metabolism is reduced, such as in patients with any disease-related or age-related cognitive decline (e.g., AD, AAMI, etc.).

[0139] The effective dose of the compound used in the composition of the present invention (i.e., a compound that can increase the concentration of ketone bodies in an amount that effectively treats or prevents loss of cognitive function caused by reduced neuronal metabolism) is obvious to those skilled in the art. As discussed above, such an effective amount can be determined based on the disclosed blood ketone levels. If the compound that can increase the concentration of ketone bodies is MCT, the MCT dose, in one embodiment, is in the range of about 0.05g / kg / day to about 10g / kg / day of MCT. In other embodiments, the dose will be in the range of about 0.25g / kg / day to about 5g / kg / day of MCT. In other embodiments, the dose will be in the range of about 0.5g / kg / day to about 2g / kg / day of MCT. In other embodiments, the dose will be in the range of about 0.1g / kg / day to about 2g / kg / day of MCT. In other embodiments, the dosage of MCT is at least about 0.05 g / kg / day, at least about 0.1 g / kg / day, at least about 0.15 g / kg / day, at least about 0.2 g / kg / day, at least about 0.5 g / kg / day, at least about 1 g / kg / day, at least about 1.5 g / kg / day, at least about 2 g / kg / day, at least about 2.5 g / kg / day, at least about 3 g / kg / day, at least about 4 g / kg / day, at least about 5 g / kg / day, at least about 10 g / kg / day, at least about 15 g / kg / day, at least about 20 g / kg / day, at least about 30 g / kg / day, at least about 40 g / kg / day, and at least about 50 g / kg / day.

[0140] Unit dose container and / or composition conveniently comprise the medicine capsule or container of spray-dried granules, tablet, capsule, lozenge, lozenge, hard candy, nutrition bar, nutrition beverage, metered spray, ointment and suppository etc.Described composition can be combined with pharmaceutically acceptable excipient such as gelatin, oil and / or other pharmaceutically active agents.Some examples of composition are described in WIPO Publication 2008 / 170235, and its entirety is incorporated by reference.For example, described composition can be advantageously combined with other therapeutic agents or preventive agents that are different from theme compound and / or used in conjunction.In many cases, the effect of such medicament can be strengthened with the combined use of theme composition.For example, described compound can be advantageously combined with antioxidant, the compound and its mixture that strengthen glucose utilization efficiency.

[0141] The daily dose of MCT can also be measured in grams of MCT per kilogram of mammal body weight (BW). The daily dose of MCT can be in the range of from about 0.01 g / kg to about 10.0 g / kg of mammal body weight. Preferably, the daily dose of MCT is from about 0.1 g / kg to about 5 g / kg of mammal body weight. More preferably, the daily dose of MCT is from about 0.2 g / kg to about 3 g / kg of mammal. More preferably, the daily dose of MCT is from about 0.5 g / kg to about 2 g / kg of mammal.

[0142] In certain embodiments, the compounds of the invention may be administered in the substantial absence of protein, or co-formulated in the absence of protein.

[0143] In certain embodiments, MCT preparations may be co-administered with proteins, or co-formulated with proteins.

[0144] In certain embodiments, MCT preparations can be co-administered with protein, or co-formulated with protein. Protein can include more than one type of protein or be different from the protein in one or more sources. Suitable protein is known in the art. If co-formulated, the amount of the protein used can include at least about 0.1g, at least about 1g, at least about 10g, at least about 50g, at least about 100g, at least about 150g, at least about 200g, at least about 250g, at least about 300g, at least about 400g. The amount of protein can be at least about 1g, at least about 50g, at least about 100g. Based on dry weight, the composition can include from about 15% to about 40% protein. Sources of such proteins include legumes, grains, dairy products, nuts, seeds, fruits, vegetables, animals, insects, synthetic sources (e.g., genetically modified yeast), or mixtures thereof. The composition also optionally comprises other components containing protein, such as dried whey and other dairy products or by-products. In certain embodiments, the MCT preparation is administered in the presence of a protein-based beverage (e.g., Ensure and similar protein-based beverages and nutritional supplements).

[0145] In addition, in certain embodiments, MCT preparations can be co-administered with carbohydrates, or co-prepared with carbohydrates.Carbohydrates can include more than one type of carbohydrate. Suitable carbohydrates are known in the art, and include monosaccharides from conventional sources (such as corn syrup, sugar beet, etc.), such as glucose, fructose, sucrose, etc. If co-prepared, the amount of carbohydrate used can include at least about 0.1g, at least about 1g, at least about 10g, at least about 50g, at least about 100g, at least about 150g, at least about 200g, at least about 250g, at least about 300g, at least about 400g. The amount of carnitine can be at least about 1g, at least about 50g, at least about 100g. Based on dry weight, the composition can include carbohydrates from about 15% to about 40%. The source of such carbohydrates includes cereals or cereals, such as rice, corn, sorghum, alfalfa, barley, soybean, rapeseed (canola), oats, wheat or its mixture. The composition may also optionally comprise other components containing carbohydrates, such as dried whey and other dairy products or by-products. Example

[0146] The following examples are included to demonstrate the preferred embodiments of the present invention. It will be appreciated by those skilled in the art that the techniques disclosed in the following examples represent techniques that the inventors have found to work well in the practice of the present invention, and therefore can be considered to constitute preferred modes of its practice. However, it will be appreciated by those skilled in the art that many changes can be made in the disclosed specific embodiments and still similar or similar results can be obtained without departing from the spirit and scope of the present invention in light of the present disclosure.

[0147] Example 1 - Comparison of serum ketone levels resulting from administration of MCT preparations, AC-1202, Axona, and AC-1204

[0148] The following study aims to demonstrate the bioequivalence (BE) of two commercial preparations of medium chain triglycerides and two inventive preparations of medium chain triglycerides (MCT). Subjects (healthy young men) were divided into four separate groups. The following preparations were orally administered to each group: Group 1, Treatment A: 10 g of commercially available CT oil; Group 2, Treatment B: 60 g AC-1202 (at least 95% tris: C8 / gum acacia); Group 3, Treatment C (40 g Axona); and Group 4, Treatment D AC-1204 (at least 95% tris: C8 / gum acacia and protein). Treatments B, C, and D were all administered with 20 grams of MCT. After administration, blood samples were obtained from each subject at different time points and evaluated using an enzymatic method (Wako Diagnostics) for measuring serum ketone levels (β-hydroxybutyrate, BHB). Figure 1 Shown are serum ketone levels in serum versus time.

[0149] like Figure 1 As shown, the two inventive formulations AC-1202 and AC-1204 achieved higher serum ketone levels (BHB) compared to the two commercial formulations. AC-1202 achieved higher BHB levels and greater C max AC-1204 produced lower BHB levels and lower C compared to AC-1202. max .

[0150] Example 2 - Comparison of MCT formulation AC-1202 administered with water or Ensure

[0151] The following study aims to demonstrate the differences in PK profiles between AC-1202 administered with water, AC-1202 administered with Ensure, and AC-1204 (a control formulation containing protein). One of the formulations was administered orally to each subject (a healthy young male). After administration, blood samples were obtained from each subject at different time points and evaluated using an enzymatic method (Wako Diagnostics) that measures serum ketone levels (β-hydroxybutyrate, BHB). Figure 2 Shown are serum ketone levels in serum versus time.

[0152] Table 1 depicts the mean BHB for subjects administered AC-1202 with water or AC1202 with Ensure at Day 45 and Day 90. In all patients, significantly higher ketone body levels were seen in AC1202+water compared to AC-1202+Ensure.

[0153] Table 1: Average BHB levels

[0154]

[0155] like Figure 2 As shown in Table 1, the AC-1202 formulation applied in water achieved the highest C max , resulting in ketone levels of 560 μM (mean with standard deviation (SE)). The control formulation AC-1204 produced less than half the serum ketone levels compared to AC-1202 administered in water.

[0156] Example 3 - Food Effect Study (FES): MCT formulation with high drug load with and without food Administration of the agent

[0157] The following study was designed to define a food effect study (FES). The MCT formulation was administered at a dose of 20 g tricaprin with and without food, without titration. In this study, two consecutive cohorts were examined. Cohort 1 subjects were Caucasian. Cohort 1 used a 4-way crossover condition. Cohort 2 subjects were Asian. Cohort 2 used a 2-way crossover condition. Based on the results of Cohort 1, the last condition in Cohort 2 was cancelled based on safety and tolerability.

[0158] Table 2 shows the experimental protocol and results used in this group.

[0159] Table 2: Experimental plan.

[0160]

[0161]

[0162] MCTs were delivered as follows: 50 g of spray dried powder containing the equivalent of 20 g of tricaprylin was shaken in approximately 180 mL of water and administered orally to the subject. Immediately after administration, the remaining treatment in the cup was shaken with an additional 60 mL of water and administered to the subject, consuming a total of approximately 240 mL of administration water per administration. The MCT formulation did not contain protein.

[0163] Tables 3-5 show the observed and adjusted pharmacokinetic values ​​(AUC, C max , T max ). Pharmacokinetic analysis was performed using non-compartmental analysis and nominal sampling times. Total ketone and BHB serum concentrations were determined enzymatically. AcAc concentrations were obtained by subtracting BHB from total ketones. If the resulting value was negative, it was set to 0. Baseline (BL) adjusted values ​​for total ketones, BHB, and AcAc in Phases 1, 2, 3, and 4 were determined using nominal time-matched correction, where each baseline time point on Day -1 of Phase 1 was subtracted from the time-matched time point on Day 1. If the nominal time 0 hour collection occurred on Day 1, Day -1 hour -1 was used as the baseline adjustment. Missing values ​​on Day -1 or Day 1 resulted in missing baseline-adjusted values ​​for that time point. For PK parameter calculations and descriptive statistics, negative values ​​resulting from baseline adjustment were set to 0. Baseline correction parameters were determined as follows: (1) C was obtained directly from the baseline-adjusted concentration-time curve max and T max ; (2) Partial AUC was calculated by subtracting the phase 1 day -1 partial AUC from the day 1 AUC of each phase. Total ketone and BHB concentrations as BLQ were set to LLOQ / 2 for acetoacetate (AcAc) determination, baseline correction, calculation of descriptive statistics, and PK parameter determination.

[0164] Using the non-compartmental method with Phoenix WinNonlin Version 6.4 or later (Certata, LP Princeton, New Jersey, United States [USA]) and / or SAS Pharmacokinetic parameters were derived using SAS, version 9.2 or higher (SAS Institute, Inc., Cary, North Carolina, USA).

[0165] Table 3: Mean values ​​and standard deviations of total ketone PK parameters.

[0166]

[0167] Table 4: Mean values ​​and standard deviations of BHB PK parameters.

[0168]

[0169] Table 5: Means and standard deviations of PK parameters for acetoacetate (AcAc)

[0170]

[0171] Figure 3A -B (total ketones), 3C-D (BHB) and 3E-F (AcAc) show the PK values ​​obtained in each cohort group after oral administration. The figure shows that the best PK was obtained by administering MCT with a standard meal. The best PK of those cohorts with good tolerance showed that MCT was administered 30 minutes after a high-fat meal, which was slightly better than administering MCT with a standard meal. Fasting while administering MCT provides poor tolerability and the lowest PK. In the well-tolerated cohorts, total ketone levels were in the range of 500-1000 μM. Finally, better PK was achieved in the Asian cohort group than in the Caucasian cohort group. The results were not corrected for BMI (body mass index).

[0172] Example 4 - Comparison of protein-based MCT formulations versus non-protein-based MCT formulations

[0173] This study aims to compare protein-based preparations with non-protein-based preparations. Fourteen subjects (healthy young men) were divided into six separate groups. One of the 6 preparations as shown in Table 5 of 20g MCT was administered orally to each group. Titration was not provided in this study. This study was a randomized, open-label and crossover design.

[0174] Table 5: Formulations used in the study

[0175]

[0176] Each formulation was orally administered at hour 0 on day 1 and approximately 30 minutes after completion of a standard meal. After administration, blood samples were obtained from each subject at various time points and evaluated using an enzymatic method (Wako Diagnostics) that measured total ketone levels, BHB (β-hydroxybutyrate) levels, and acetoacetate (AcAc) level estimates. The data from these enzymatic assays are shown in Figures 4-7B. As shown in the above figures, AC-1202 achieved an increased C max , the earliest T max The protein-based formulations (MCT procal, tricaprylin / milk-Cunnane, and AC-1207) had reasonable AUCs but delayed and lower C max The protein formulation appeared to delay the release of MCT. The carbohydrate / gum arabic based formulation provided a more rapid release of MCT.

[0177] This application also includes the following specific implementation schemes:

[0178] 1. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the substantial absence of protein, the MCT composition provides a maximum serum concentration (C 60.3% to 80.7% of total ketones) for at least 3 hours after administration. max ).

[0179] 2. The method of embodiment 1, wherein the MCT composition provides a maximum serum concentration (C ) of total ketones within at least 2.5 hours after administration, at least 2 hours after administration, at least 1.5 hours after administration, or at least 1 hour after administration. max ).

[0180] 3. The method described in any of the above specific embodiments, wherein the therapeutically effective amount of MCT is 20 g and the C of total ketones is max It is at least 400 μmol / L, at least 450 μmol / L or at least 500 μmol / L.

[0181] 4. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the substantial absence of protein, the MCT composition provides a maximum serum concentration (C 250 of β-hydroxybutyrate (BHB) for at least 3 hours after administration. max ).

[0182] 5. The method of embodiment 4, wherein the MCT composition provides a maximum serum concentration (C ) of BHB at least 2.5 hours after administration, at least 2 hours after administration, at least 1.5 hours after administration, or at least 1 hour after administration. max ).

[0183] 6. The method according to any one of specific embodiments 4 or 5, wherein the therapeutically effective amount of MCT is 20 g and wherein the C of BHB is max It is at least 400 μmol / L, at least 450 μmol / L or at least 500 μmol / L.

[0184] 7. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the substantial absence of protein, the MCT composition provides a maximum serum concentration (C ) of acetoacetate (AcAc) for at least 2.5 hours after administration. max ).

[0185] 8. The method according to embodiment 7, wherein the MCT composition provides a maximum serum concentration (C ) of AcAc within at least 2 hours after administration, at least 1.5 hours after administration, or at least 1 hour after administration. max ).

[0186] 9. The method according to any one of specific embodiments 7 or 8, wherein the therapeutically effective amount of MCT is 20 g and wherein the C of AcAc is max It is at least 50 μmol / L, at least 60 μmol / L, at least 70 μmol / L, at least 80 μmol / L, at least 90 μmol / L or at least 100 μmol / L.

[0187] 10. The method according to any one of embodiments 1-9, wherein the MCT pharmaceutical composition is stable at a pH of about 1 to about 3.

[0188] 11. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the presence of protein, the MCT composition provides a maximum serum concentration (C 20 of total ketones) at least 2.5 hours after administration. max ).

[0189] 12. The method of embodiment 11, wherein the MCT composition provides a maximum serum concentration (C ) of total ketones at least 3.0 hours after administration, at least 3.5 hours after administration, at least 4.0 hours after administration, or at least 5 hours after administration. max ).

[0190] 13. The method according to any one of specific embodiments 11 or 12, wherein the therapeutically effective amount of MCT is 20 g and wherein the C of total ketones is max It is at least 200 μmol / L, at least 250 μmol / L, at least 300 μmol / L or at least 350 μmol / L.

[0191] 14. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the presence of protein, the MCT composition provides a maximum serum concentration (C 200 of β-hydroxybutyrate (BHB)) at least 2.5 hours after administration. max ).

[0192] 15. The method of embodiment 14, wherein the MCT composition provides a maximum serum concentration (C ) of BHB at least 3.0 hours after administration, at least 3.5 hours after administration, at least 4.0 hours after administration, or at least 5 hours after administration. max ).

[0193] 16. The method according to any one of specific embodiments 14 or 15, wherein the therapeutically effective amount of MCT is 20 g and wherein the C of BHB is max It is at least 200 μmol / L, at least 250 μmol / L, at least 300 μmol / L or at least 350 μmol / L.

[0194] 17. A method of treating a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the presence of protein, the MCT composition provides a maximum serum concentration (C 200 of acetoacetate (AcAc)) of at least 2.5 hours after administration. max ).

[0195] 18. The method of embodiment 17, wherein the MCT composition provides a maximum serum concentration (C ) of AcAc at least 3.0 hours after administration, at least 3.5 hours after administration, at least 4.0 hours after administration, or at least 5 hours after administration.max ).

[0196] 19. The method according to any one of embodiments 17 or 18, wherein the therapeutically effective amount of MCT is 20 g and wherein the C of AcAc is max It is at least 20 μmol / L, at least 25 μmol / L, at least 30 μmol / L, at least 35 μmol / L or at least 40 μmol / L.

[0197] 20. The method according to any one of embodiments 11-19, wherein the MCT pharmaceutical composition is stable at a pH of about 5 to about 7.

[0198] 21. A method of treating a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in two portions,

[0199] wherein the first portion comprises a first therapeutically effective amount of medium chain triglycerides (MCTs) that are substantially released within 3 hours after administration to a subject, and

[0200] The second portion comprises a second therapeutically effective amount of medium chain triglycerides (MCTs) and a protein, wherein the second amount of MCTs is substantially released from the second portion over a period of 3 hours or more after the second portion is administered to a subject.

[0201] 22. The method according to embodiment 21, wherein the first portion of MCTs is administered in the substantial absence of protein.

[0202] 23. The method of any one of embodiments 21 or 22, wherein the first portion of MCTs is substantially released within 2.5 hours, within 2 hours, within 1.5 hours, or within 1 hour after administration to a subject.

[0203] 24. The method of any one of embodiments 21-23, wherein the second portion of MCTs is substantially released over 3.5 or more hours, 4 or more hours, 4.5 or more hours, or 5 or more hours after administration to a subject.

[0204] 25. The method of any one of the preceding specific embodiments, wherein the disease or disorder is a disease or disorder associated with a decline in cognitive function.

[0205] 26. The method according to embodiment 25, wherein the disease or disorder associated with a decline in cognitive function is selected from Alzheimer's disease and age-related memory impairment.

[0206] 27. The method of any of the preceding specific embodiments, wherein the subject lacks the ApoE4 genotype.

[0207] 28. The method of any of the preceding specific embodiments, wherein the amount of total ketones, BHB and / or AcAc is determined using an enzymatic method.

[0208] 29. A pharmaceutical composition comprising a first component and a second component,

[0209] wherein the first component comprises a therapeutically effective amount of a first portion of medium chain triglycerides (MCTs) that are substantially released within 3 hours after the pharmaceutical composition is administered to a subject in need thereof, and

[0210] The second component comprises a therapeutically effective amount of a second portion of medium chain triglycerides (MCTs) and a protein, wherein the second portion of MCTs is substantially released from the second component over a period of 3 hours or more after the pharmaceutical composition is administered to a subject.

[0211] 30. The pharmaceutical composition according to embodiment 29, wherein the first portion of MCT is substantially released within 2.5 hours, 2 hours, 1.5 hours or 0.5 hours of administration of the pharmaceutical composition.

[0212] 31. A pharmaceutical composition comprising:

[0213] Medium chain triglycerides (MCT) and at least one pharmaceutically acceptable excipient,

[0214] wherein the composition is substantially free of protein,

[0215] wherein when administered to a subject in need thereof 30 minutes after a standard meal and in the substantial absence of protein, the composition provides a maximum serum concentration (C ) of at least one ketone body for at least 3 hours after administration. max ).

[0216] 32. The composition of embodiment 31, wherein the MCT composition provides a maximum serum concentration (C ) of at least one ketone body within at least 2.5 hours after administration, at least 2 hours after administration, at least 1.5 hours after administration, or at least 1 hour after administration. max ).

[0217] 33. The composition according to embodiment 31 or 33, wherein the at least one ketone body is b-hydroxybutyrate (BHB), acetoacetate (AcAc), or a combination thereof.

[0218] 34. The method or composition of any one of the preceding specific embodiments, wherein the MCT pharmaceutical composition is an emulsion.

[0219] 35. The method or composition of embodiment 34, wherein the emulsion does not phase separate for at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 45 minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 5 hours, or at least 24 hours.

[0220] 36. The method or composition of any one of embodiments 34 or 35, wherein the emulsion has an average droplet diameter between about 100 nm to about 1000 nm, about 100 nm to about 500 nm, or about 200 nm to about 300 nm.

[0221] 37. The method or composition of any of the preceding specific embodiments, wherein the MCT pharmaceutical composition comprises at least 95% tri:C8 MCT.

[0222] 38. The method or composition of any of the preceding specific embodiments, wherein the MCT pharmaceutical composition comprises at least 98% tri:C8 MCT.

[0223] 39. The method or composition of any of the preceding specific embodiments, wherein the MCT pharmaceutical composition comprises at least 95% caprylic triglyceride.

[0224] 40. The method or composition of any one of the preceding specific embodiments, wherein the MCT pharmaceutical composition comprises at least 98% caprylic triglyceride.

[0225] 41. The method or composition of any one of the preceding specific embodiments, wherein the subject is a human.

Claims

1. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the substantial absence of protein, the MCT composition provides a maximum serum concentration (C 60.3% to 80.7% of total ketones) for at least 3 hours after administration. max ).

2. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the substantial absence of protein, the MCT composition provides a maximum serum concentration (C 200 of β-hydroxybutyrate (BHB) for at least 3 hours after administration. max ).

3. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the substantial absence of protein, the MCT composition provides a maximum serum concentration (C ) of acetoacetate (AcAc) for at least 2.5 hours after administration. max ).

4. The method of any one of claims 1-3, wherein the MCT pharmaceutical composition is stable at a pH of about 1 to about 3.

5. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the presence of protein, the MCT composition provides a maximum serum concentration (C 20 of total ketones) at least 2.5 hours after administration. max ).

6. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the presence of protein, the MCT composition provides a maximum serum concentration (C 200 of β-hydroxybutyrate (BHB)) at least 2.5 hours after administration. max ).

7. A method of treating a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in a pharmaceutical composition, wherein when administered 30 minutes after a standard meal and in the presence of protein, the MCT composition provides a maximum serum concentration (C ) of acetoacetate (AcAc) at least 2.5 hours after administration. max ).

8. A method of treating a subject in need thereof, the method comprising administering a therapeutically effective amount of medium chain triglycerides (MCTs), wherein the therapeutically effective amount of MCTs is administered in two portions, wherein the first portion comprises a first therapeutically effective amount of medium chain triglycerides (MCTs) that are substantially released within 3 hours after administration to a subject, and The second portion comprises a second therapeutically effective amount of medium chain triglycerides (MCTs) and a protein, wherein the second amount of MCTs is substantially released from the second portion over a period of 3 hours or more after the second portion is administered to a subject.

9. A pharmaceutical composition comprising a first component and a second component, wherein the first component comprises a therapeutically effective amount of a first portion of medium chain triglycerides (MCTs) that are substantially released within 3 hours after the pharmaceutical composition is administered to a subject in need thereof, and The second component comprises a therapeutically effective amount of a second portion of medium chain triglycerides (MCTs) and a protein, wherein the second portion of MCTs is substantially released from the second component over a period of 3 hours or more after the pharmaceutical composition is administered to a subject.

10. A pharmaceutical composition comprising: Medium chain triglycerides (MCT) and at least one pharmaceutically acceptable excipient, wherein the composition is substantially free of protein, wherein when administered to a subject in need thereof 30 minutes after a standard meal and in the substantial absence of protein, the composition provides a maximum serum concentration (C ) of at least one ketone body for at least 3 hours after administration. max ).

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