Method for delivering medium-chain triglycerides with controlled pharmacokinetic, safety, and tolerable profiles.

Abstract

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

Description

[Technical Field]

[0001] Cross-reference of related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 089,797, filed on 9 October 2020, the disclosure of which is incorporated herein by reference in its entirety.

[0002]

[0002] This disclosure relates to a method for delivering a pharmaceutical composition containing a high drug load of medium-chain triglycerides to a target that requires it. [Background technology]

[0003]

[0003] Medium-chain triglycerides (MCTs) contain fatty acids having a chain length of 5 to 12 carbon atoms. MCTs have been extensively studied and have known nutritional and pharmaceutical uses. MCTs have a melting point in which they are liquid at room temperature. Furthermore, MCTs are relatively small, ionizable under physiological conditions, and generally soluble in aqueous solutions.

[0004]

[0004] When intended to be used as a pharmaceutical composition, specific pharmacokinetic properties (e.g., C) may be used based on the intended treatment. max , T max It is often desirable to achieve (and so on).

[0005]

[0005] Therefore, there is a need in the art for a pharmaceutical composition of MCT that achieves specific pharmacokinetic properties. [Overview of the project]

[0006]

[0006] In one aspect, the present disclosure relates to a method for administering tricaprlin to a subject in need for the treatment of a disease or disorder. In a particular embodiment, the method comprises the step of administering a pharmaceutical composition comprising a therapeutically effective dose of tricaprlin to a subject in need, wherein the therapeutically effective dose of tricaprlin is at least 300 μmol / L of the maximum serum concentration of total ketones (C max ) provides. In a particular embodiment, total ketones C maxThe concentration is at least 500 μmol / L, at least 750 μmol / L, or at least 1000 μmol / L.

[0007]

[0007] In a particular embodiment, the therapeutically effective dose of tricaprine is 30g to 80g per day, administered as a single dose or in divided doses.

[0008] In some embodiments, the therapeutically effective dose of tricaprylin is at least 500 ng / mL of tricaprylin C max To provide.

[0008]

[0009] In certain embodiments, the therapeutically effective dose of tricaprine is such that the maximum serum concentration of total ketones (C) is reached at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours after administration. max ) provides.

[0009]

[0010] In certain embodiments, the subjects requiring it are elderly subjects. In certain embodiments, elderly subjects lack the ApoE4 genotype.

[0011] In certain embodiments, the therapeutically effective dose of tricaprylin is at least 400 μmol / L, at least 450 μmol / L, or at least 500 μmol / L of β-hydroxybutyrate (BHB). max To provide.

[0010]

[0012] In certain embodiments, the therapeutically effective dose of tricaprylin is at least 50 umol / L, at least 60 umol / L, at least 70 umol / L, at least 80 umol / L, at least 90 umol / L, or at least 100 umol / L of acetoacetate (AcAc) C max To provide.

[0011]

[0013] In certain embodiments, a disease or disorder is a disease or disorder associated with cognitive decline. In certain embodiments, a disease or disorder associated with cognitive decline is selected from Alzheimer's disease and age-related memory impairment.

[0012]

[0014] In certain embodiments, the pharmaceutical composition is formed as an emulsion for administration.

[0015] In certain embodiments, a therapeutically effective dose of 30 g to 80 g of tricaprylin per day is achieved by titrating up to the final therapeutically effective dose. In certain embodiments, the titration is performed over 2 to 4 weeks by adjusting the dose of tricaprylin by 5 g to 10 g per week.

[0013]

[0016] In certain embodiments, the pharmaceutical composition is administered such that no ethnicity effect on the total ketone C max exposure is observed in white versus Asian subjects.

[0014]

[0017] While numerous embodiments are disclosed, still 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. As will be understood, the invention is capable of modifications in various aspects without departing from the spirit and scope of the present disclosure. Accordingly, the detailed description is to be regarded as illustrative in nature and not restrictive.

Brief Description of the Drawings

[0015] [Figure 1]

[0018] A graph showing various BHB concentrations for various formulations in a human PK study according to embodiments of the present disclosure is illustrated. [Figure 2]

[0019] A graph showing various BHB concentrations for various formulations in a rat PK study according to embodiments of the present disclosure is illustrated. [Figure 3]

[0020] A model showing the AcAc brain metabolic rate over time for varying doses of tricaprylin according to embodiments of the present disclosure is illustrated. [Figure 4]

[0021] A graph showing the mean (±SD) plasma total ketone concentration over time according to embodiments of the present disclosure is illustrated. [Figure 5]

[0022] A graph showing mean (±SD) unadjusted total ketone plasma concentration - linear scale - overall, in accordance with aspects of this disclosure, is provided. [Figure 6]

[0023] A graph showing the mean (±SD) unadjusted tricaprylin plasma concentration-linear scale-overall, in accordance with aspects of this disclosure, is provided. [Figure 7]

[0024] Mean (±SD) unadjusted plasma octanoate concentration - linear scale - overall, in accordance with aspects of this disclosure. [Figure 8]

[0025] A graph showing the mean unadjusted PK concentration, total, and total ketones (μM) (PK population) according to an aspect of this disclosure is provided. [Figure 9]

[0026] A graph showing the mean unadjusted PK concentration - total - tricaprylin (ng / mL) (PK population) according to an aspect of this disclosure is provided. [Figure 10]

[0027] A graph showing the mean unadjusted PK concentration - total - octanoic acid (μM) (PK population) according to an aspect of this disclosure is provided. [Figure 11]

[0028] A graph showing the mean total plasma ketone concentration, according to an aspect of this disclosure, is shown. [Figure 12A]

[0029] Figure 12A shows a scattering plot of total ketone Cmax after a single dose of 50 g AC-SD-03 (20 g tricaprylin) in healthy Chinese (n-18) or Caucasian (n=14) subjects, according to an aspect of this disclosure, and Figure 12B shows a scattering plot of total ketone AUC0-t after a single dose of 50 g AC-SD-03 (20 g tricaprylin) in healthy Chinese (n=18) or Caucasian (n=14) subjects, according to an aspect of this disclosure. [Figure 12B]

[0029] Figure 12A shows a scattering plot of total ketone Cmax after a single dose of 50 g AC-SD-03 (20 g tricapriline) in healthy Chinese (n-18) or Caucasian (n=14) subjects according to an aspect of the present disclosure, and Figure 12B shows a scattering plot of total ketone AUC0-t after a single dose of 50 g AC-SD-03 (20 g tricapriline) in healthy Chinese (n=18) or Caucasian (n=14) subjects according to an aspect of the present disclosure. [Figure 13]

[0030] The generally understood in vivo metabolism of MCTs, as described in this disclosure, is illustrated. [Modes for carrying out the invention]

[0016]

[0031] The brain is highly metabolic, and therefore any deficiency in its metabolism leads to energy stress and ultimately cell death. Normally, the brain relies almost entirely on glucose as its energy substrate. Although the brain accounts for only 2% of body weight, it utilizes 25% of the body's glucose (approximately 120g / day), receives 15% of cardiac output, and uses 20% of the body's oxygen. Therefore, the body has highly conserved physiological mechanisms for utilizing ketone bodies as an alternative energy substrate when glucose availability is low.

[0017]

[0032] Based on the mechanism of action of ketone bodies as an alternative fuel source for brain cells that cannot efficiently metabolize glucose, this disclosure unexpectedly finds that optimized methods for administering MCTs can be achieved to provide a controlled pharmacokinetic profile and outcomes. For example, the optimized method can achieve a desired maximum (or peak) concentration (C) of the activator MCT and the active metabolite ketone body in vivo formation. max ) and C max The desired time to reach (T) max) can be provided with a controlled pharmacokinetic profile. More specifically, it has been found that the pharmacokinetic profiles of MCT and the in vivo formation of the active metabolite ketone body can be controlled. In yet another aspect, the method of the present disclosure can provide a controlled pharmacokinetic profile (e.g., total ketone C after administration of tricaprylin). max It was found that the influence of ethnicity on exposure levels was not observed in the clinical outcomes compared to the Caucasian vs. Asian population.

[0018]

[0033] MCTs containing caprylic acid triglycerides or tricaprylin, as described herein, are ketone-producing agents for the treatment of, for example, mild to moderate Alzheimer's disease (AD). However, this disclosure is not limited in that sense, and the methods of administration disclosed may be used to treat any disease, condition, or disorder for which ketone-producing effects can be beneficial. In accordance with aspects of this disclosure, tricaprylin may be administered in high doses to compensate for the localized cerebral glucose metabolism reduction characteristic of AD and other diseases, conditions, and disorders. After ingestion, tricaprylin induces ketosis. Without intending to be bound by theory, it has been found that the formulation of tricaprylin can affect the digestion and absorption of the drug, and therefore, changes in formulation can affect clinical outcomes. For background, the in vivo metabolism of MCTs is illustrated in Figure 13.

[0019]

[0034] In one embodiment, a disclosed method of administering tricaprline, which provides a controlled pharmacokinetic profile, can result in an increase in ketone concentrations in the body. Tricaprline may be administered in an amount effective in inducing hyperketonemia. In one embodiment, hyperketonemia leads to the utilization of ketone bodies as energy in the brain.

[0020]

[0035] In one embodiment, the method may administer tricaprlin as a pharmaceutical formulation to provide a controlled circulating concentration of MCT, for example, tricaprlin, in a subject. The amount of circulating MCT can be measured at several times after administration, and in one embodiment, the peak concentration (C) in serum and / or plasma. max These measurements are taken at times predicted to be close to the predicted peak serum and / or plasma concentration levels, but may be taken before or after the predicted peak serum and / or plasma concentration levels. The amounts measured during these off-peak times are then optionally adjusted to reflect the predicted levels at the predicted peak time.

[0021]

[0036] In one embodiment, the peak serum concentration (C) reached of tricaprylin or octanoic acid (OA), which are MCT compounds absorbed from the intestines. max The peak serum concentration of tricaprylin (C) is approximately 350 ng / mL to approximately 1500 ng / mL. In other embodiments, the peak serum concentration of tricaprylin (C) is approximately 350 ng / mL to approximately 1500 ng / mL. max The peak serum concentration of tricaprylin (C) is approximately 350-1200 ng / mL, approximately 350-1000 ng / mL, approximately 350-950 ng / mL, etc., but as shown above, variations will inevitably occur depending on the composition and the subject. In some embodiments, the peak serum concentration of tricaprylin (C) is max The peak serum concentration of tricaprylin (C) is approximately 400 to 1000 ng / mL. In other embodiments, the peak serum concentration of tricaprylin (C) is approximately 400 to 1000 ng / mL. max The ) is at least 450 ng / mL, at least 500 ng / mL, at least 550 ng / mL, at least 600 ng / mL, at least 650 ng / mL, at least 700 ng / mL, at least 800 ng / mL, at least 850 ng / mL, at least 900 ng / mL, at least 950 ng / mL, or at least 1000 ng / mL.

[0022]

[0037] In one embodiment, tricaprylin C max Time to reach (T max The time to administration is approximately 0.5 hours to 3 hours after administration, for example, approximately 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours. In another embodiment, the C of MCT max Time to reach (T max) is approximately 1 to 2.5 hours. In another aspect, the C of MCT max Time to reach (T max ) is approximately 1 to 2 hours. In another embodiment, C max Time to reach (T max ) is approximately 0.5 hours to approximately 1.5 hours. In another aspect, the C of MCT max Time to reach (T max ) are approximately 0.5 hours, approximately 1 hour, approximately 1.5 hours, approximately 2 hours, approximately 2.5 hours, or approximately 3 hours. In another embodiment, the C of MCT max Time to reach (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.

[0023]

[0038] In one aspect, the peak serum concentration of total ketones reached (C max ) is approximately 350 micromol / liter (μmol / L) to approximately 1500 μmol / L. In other embodiments, the peak serum concentration of total ketone bodies (C) max ) are approximately 350 to 1200 μmol / L, 350 to 1000 μmol / L, 450 to 1200 μmol / L, 500 to 1200 μmol / L, 500 to 1000 μmol / L, etc., but as shown above, variations will inevitably occur depending on the composition and the subject. In other embodiments, the peak serum concentration of total ketone bodies (C) max ) is at least 450 μmol / L, at least 500 μmol / L, at least 550 μmol / L, at least 600 μmol / L, at least 650 μmol / L, at least 700 μmol / L, at least 800 μmol / L, at least μmol / L, at least 900 μmol / L, at least 950 μmol / L, or at least 1000 μmol / L.

[0024]

[0039] In one aspect, the total ketone body C max Time to reach (T max ) is approximately 0.5 hours to approximately 3 hours. In another aspect, total ketone bodies C max Time to reach (T max) is approximately 1 to 2.5 hours. In another aspect, total ketone bodies C max Time to reach (T max ) is approximately 1 to 2 hours. In another embodiment, C max Time to reach (T max ) is approximately 0.5 hours to approximately 1.5 hours. In another aspect, total ketone body C max Time to reach (T max ) are approximately 0.5 hours, approximately 1 hour, approximately 1.5 hours, approximately 2 hours, approximately 2.5 hours, or approximately 3 hours. In another embodiment, total ketone bodies C max Time to reach (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 some embodiments, total ketone body C max Time to reach (T max ) is approximately 1 hour. In some embodiments, the total ketone body C max Time to reach (T max ) is approximately 1.5 hours. In some embodiments, total ketone bodies C max Time to reach (T max ) is approximately 2 hours.

[0025]

[0040] In one embodiment, a disclosed method for administering tricaprin can provide a controlled circulating concentration of at least one ketone body in a subject, comprising total ketone bodies, beta-hydroxybutyrate (BHB), and / or acetoacetate (AcAc). The amount of circulating ketone bodies can be measured at several times after administration, and in one embodiment, the peak concentration (C) in serum and / or plasma can be measured. max These measurements are taken at times predicted to be close to the predicted peak serum and / or plasma concentration levels, but may be taken before or after the predicted peak serum and / or plasma concentration levels. The amounts measured during these off-peak times are then optionally adjusted to reflect the predicted levels at the predicted peak time.

[0026]

[0041] In one embodiment, the peak serum concentration (C) of at least one ketone body (including total ketone bodies, beta-hydroxybutyrate (BHB), octanoic acid, and / or acetoacetate (AcAc)) is reached. max ) is approximately 350 micromol / liter (μmol / L) to approximately 1000 μmol / L. In other embodiments, the peak serum concentration (C) of at least one ketone body is max ) is approximately 350-950 μmol / L, approximately 350-900 μmol / L, approximately 350-850 μmol / L, approximately 350-800 μmol / L, approximately 350-750 μmol / L, approximately 350-700 μmol / L, approximately 350-650 μmol / L, approximately 350-550 μmol / L, approximately 350-500 μmol / L, or approximately 350-800 μmol / L, but as shown above, variations will inevitably occur depending on the composition and subject. In other embodiments, the peak serum concentration (C) of at least one ketone body is max ) is approximately 400-950 μmol / L, approximately 400-900 μmol / L, approximately 400-850 μmol / L, approximately 400-800 μmol / L, approximately 400-750 μmol / L, approximately 400-700 μmol / L, approximately 400-650 μmol / L, approximately 400-600 μmol / L, or approximately 400-550 μmol / L. In some embodiments, the peak serum concentration (C) of at least one ketone body is approximately 400-950 μmol / L, approximately 400-900 μmol / L, approximately 400-850 μmol / L, approximately 400-700 μmol / L, approximately 400-650 μmol / L, or approximately 400-550 μmol / L. max ) is approximately 400 to approximately 600 μmol / L. In other embodiments, the peak serum concentration (C) of at least one ketone body is max ) is approximately 450 to approximately 550 μmol / L. In other embodiments, the peak serum concentration (C) of at least one ketone body is max The peak serum concentration (C) 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. In other embodiments, the peak serum concentration (C) 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. maxThe concentrations are approximately 20-180 μmol / L, 20-160 μmol / L, 20-140 μmol / L, 20-120 μmol / L, 20-100 μmol / L, 20-80 μmol / L, 20-60 μmol / L, or 20-40 μmol / L, but as shown above, variations will inevitably occur depending on the composition and the target.

[0027]

[0042] In one embodiment, at least one type of ketone body C max Time to reach (T max The time to administration is approximately 0.5 hours to approximately 3 hours, for example, approximately 30 minutes, approximately 45 minutes, approximately 1 hour, approximately 1.5 hours, approximately 2 hours, approximately 2.5 hours, or approximately 3 hours. In another embodiment, at least one ketone body C max Time to reach (T max The incubation period is approximately 1 to 2.5 hours. In another embodiment, at least one ketone body C max Time to reach (T max ) is approximately 1 to 2 hours. In another embodiment, C of at least one ketone body max Time to reach (T max ) is approximately 0.5 hours to approximately 1.5 hours. In another embodiment, at least one ketone body C max Time to reach (T max ) are approximately 0.5 hours, approximately 1 hour, approximately 1.5 hours, approximately 2 hours, approximately 2.5 hours, or approximately 3 hours. In another embodiment, at least one ketone body C max Time to reach (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 some embodiments, at least one ketone body C max Time to reach (T max ) is approximately 1 hour. In some embodiments, at least one type of ketone body C max Time to reach (T max ) is approximately 1.5 hours. In some embodiments, at least one ketone body C max Time to reach (T max ) is approximately 2 hours.

[0028]

[0043] In another aspect, the method of the present disclosure has been found to achieve clinical outcomes in which ethnic influences on the pharmacokinetic profile are not observed in Caucasian versus Asian subjects. For example, tricaprin C after administration of tricaprin. max and T max Value, total ketone C max and T max The value, or the C of ketone bodies (e.g., BHB and AcAc). max and T max No significant differences were observed in the values.

[0029]

[0044] Several definitions are provided herein. Such definitions are intended to include grammatical equivalents. Unless the context should be otherwise interpreted, singular terms as used herein and in the claims include plural forms, and plural terms include singular forms. Unless otherwise stated, the use of “or” means “and / or.” Furthermore, the use of terms such as “comprising,” “having,” “including,” and other forms such as “includes” and “included” is intended to be comprehensive and means that there may be additional elements other than those listed. Also, terms such as “element” or “component” include both elements and components that constitute one unit and elements and components that constitute one or more subunits, unless otherwise specifically stated.

[0030]

[0045] As used herein, “administration” includes, as understood by those skilled in the art, in vivo settings such as the gastrointestinal tract, delivery by ingestion or swallowing, or other such means for delivering the pharmaceutical composition. See, for example, Remington: The Science and Practice of Pharmacy, 20th edition (2000). If the aqueous setting is in vitro, “administration” means placement or delivery of the pharmaceutical composition into an in vitro test medium.

[0031]

[0046] As used herein, unless otherwise specified, "weight %" refers to "weight % of the total composition".

[0047] It is acknowledged by those skilled in the art that, in some circumstances, the analysis of ketone body measurement / quantification may be adjusted to account for errors, baseline measurements, etc. The amounts of one or more ketone bodies may be determined from whole blood, plasma, serum, and / or combinations thereof. The amounts of one or more ketone bodies may be determined by methods known to those skilled in the art, including, but not limited to, enzyme assays and liquid chromatography-tandem mass spectrometry (LC-MS).

[0032]

[0048] Pharmaceutical compositions useful with respect to the methods of the present disclosure generally contain a high load of an activator comprising at least one MCT. According to certain aspects of the present disclosure, the pharmaceutical compositions of the present disclosure may contain an activator comprising or essentially derived from an MCT, which is referred to herein as caprylic acid triglyceride or tricaprylin ("CT"), having more than about 95% C8, for example, 98%, 99%, and 99.5% or more C8 in R1, R2, and R3. In certain aspects, the MCT is caprylic acid triglyceride or tricaprylin 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 and can be made by the semi-synthetic esterification of octanoic acid to glycerin, etc.

[0033]

[0049] In other embodiments, the pharmaceutical composition may contain or an activator essentially derived from MCTs in which R1, R2, and R3 are fatty acids containing a 6-carbon back chain (tri-C6:0). Tri-C6:0 MCTs are absorbed very rapidly by the gastrointestinal tract in several animal model systems. The high absorption rate results in rapid hepatic perfusion and a potent ketone production reaction. In yet another embodiment, the pharmaceutical composition may contain or an activator essentially derived from MCTs in which R1, R2, and R3 are fatty acids containing an 8-carbon back chain (tri-C8:0). In yet another embodiment, the pharmaceutical composition may contain or an activator essentially derived from MCTs in which R1, R2, and R3 are fatty acids containing a 10-carbon back chain (tri-C10:0). In yet another embodiment, the pharmaceutical composition may contain MCTs in which R1, R2, and R3 are a mixture of C8:0 and C10:0 fatty acids. In another embodiment, the pharmaceutical composition may contain or an activator essentially derived from MCTs in which R1, R2, and R3 are a mixture of C6:0, C8:0, C10:0, and C12:0 fatty acids. In yet another embodiment, the pharmaceutical composition may contain or an activator essentially derived from MCTs in which more than 95% of R1, R2, and R3 are 8-carbon long. In yet another embodiment, the pharmaceutical composition may contain or an activator essentially derived from MCTs in which R1, R2, and R3 carbon chains are 6-carbon or 10-carbon chains. In yet another embodiment, the pharmaceutical composition may contain or an activator essentially derived from MCTs in which about 50% of R1, R2, and R3 are 8-carbon long and about 50% of R1, R2, and R3 are 10-carbon long. In one embodiment, the pharmaceutical composition may contain or an activator essentially derived from MCTs in which R1, R2, and R3 are 6, 7, 8, 9, 10, or 12-carbon chain lengths, or a mixture thereof.

[0034]

[0050] In certain embodiments, the pharmaceutical composition may contain a high drug load of an activator comprising or essentially derived from at least one MCT, such as tricaprylin, in amounts of at least about 30% by weight of the total composition, at least about 35% of the total composition, at least about 40% by weight of the total composition, about 30% to about 65% of the total composition, about 30% to about 60% of the total composition, about 35% to about 60% of the total composition, about 40% to about 55% of the total composition, or about 40% to about 50% of the total composition.

[0035]

[0051] In certain aspects, the pharmaceutical compositions of this disclosure may include a high drug load of an activator comprising or essentially comprising at least one MCT, at least one surfactant, and optionally an adsorbent and / or a film-forming polymer. The pharmaceutical compositions may also include co-surfactants. In some embodiments, the pharmaceutical compositions comprise at least two surfactants. In certain embodiments, the composition is a self-emulsifying spray-drying composition.

[0036]

[0052] In other aspects, at least one surfactant is selected from polyoxyl hydrogenated castor oil, polyoxyl stearate, polyoxyl hydroxystearate, lecithin, phosphatidylcholine, and combinations thereof. In certain embodiments, the solid composition contains at least two surfactants which may be selected from polyoxyl hydrogenated castor oil, polyoxyl stearate, polyoxyl hydroxystearate, lecithin, phosphatidylcholine, and combinations thereof. In certain embodiments, at least one of the at least two surfactants is a polyoxyl hydrogenated castor oil or polyoxyl stearate surfactant. The at least two surfactants may be present in a ratio of 2:1 to 1:1 relative to each other.

[0037]

[0053] In certain aspects, adsorbents include silica compounds, such as colloidal silicon dioxide (AEROSIL®, CAB-O-SIL®), amorphous silica gel (SYLOID®, SYLYSIA®), granular silicon dioxide (AEROPERL®), silica aerogel, magnesium aluminometasilicate (NEUILIN®), calcium silicate (FLORITE®), and regular mesoporous silicates.

[0038]

[0054] In certain aspects, the film-forming polymer may be polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), or dextran with varying molecular weights (e.g., 10,000, 40,000, 70,000, 500,000, etc.). In certain embodiments, the film-forming polymer is PVP or PVP-VA, and in other embodiments, the film-forming polymer is PVP-VA.

[0039]

[0055] In other respects, the pharmaceutical compositions of this disclosure may include spray-dried particles having average diameters such as approximately 5 μm to approximately 50 μm, approximately 5 μm to approximately 30 μm, approximately 5 μm to approximately 20 μm, and approximately 5 μm to approximately 10 μm.

[0040]

[0056] In other aspects, the pharmaceutical compositions of this disclosure form emulsions in an aqueous environment that are stable for at least about 4 hours under ambient conditions. In certain embodiments, the emulsions may have an average droplet diameter less than about 1000 nm but greater than about 100 nm, for example, about 100 nm to 500 nm, about 200 nm to about 300 nm, or about 160 nm to about 190 nm.

[0041]

[0057] In certain aspects, tricaprilin may be administered in a pharmaceutical composition comprising a high drug load of tricaprilin and one or more emulsion-forming excipients present in concentrations sufficient to form an emulsion at room temperature. The pharmaceutical composition may contain the components in amounts as described herein. In some embodiments, the pharmaceutical composition may form a stable liquid emulsion.

[0042]

[0058] As described herein, the pharmaceutical compositions of this disclosure may form liquid emulsions. The emulsion refers to a composition that, when diluted with water or other aqueous medium and gently mixed, produces a stable oil / water emulsion having an average droplet diameter of less than about 5 μm but greater than about 100 nm (e.g., 0.35–1.2 μm), and is generally polydisperse. Such emulsions are stable, meaning there is no visible or detectable phase separation and no visible or detectable crystallization.

[0043]

[0059] When used herein, "gently mixed" is understood in the art to mean the formation of an emulsion by gentle manual (or mechanical) mixing, such as by repeated inversion in a standard laboratory mixer. High shear mixing is not required to form an emulsion. Such emulsion compositions generally emulsify almost spontaneously when introduced into an aqueous environment.

[0044]

[0060] As described above, the pharmaceutical compositions of this disclosure can form stable emulsions when administered in an aqueous environment, for example, in water, a pharmaceutically appropriate aqueous solution, or in vivo. For example, the emulsion may be stable under ambient conditions for at least about 24 hours, at least about 1 day, at least about 5 days, at least about 10 days, at least about 1 month, etc. In certain embodiments, the formed emulsion does not undergo phase separation during the duration of its stability. In certain embodiments, the emulsion may have an average droplet diameter of less than about 5 μm but greater than about 100 nm (e.g., 0.35 to 1.2 μm).

[0045]

[0061] In certain embodiments, the formed emulsion may be stable at the pH of the stomach, e.g., pH approximately 1–3, pH approximately 1.2–2.9, etc. In certain embodiments, the formed emulsion may be stable at the pH of the intestine and / or colon, e.g., pH approximately 5–7, pH approximately 5.5–6.9, etc. In certain embodiments, the formed emulsion may begin to decompose or undergo phase separation at the pH of the stomach after approximately 1 / 2–1 hour, but will not release the encapsulated tricaprylin until reaching the pH of the intestine or colon. In this regard, without intending to be bound by theory, in-vitro digestion assays demonstrate that the encapsulated tricaprylin is released from the emulsion at the pH of the intestine and / or colon, which is the first site for lipid digestive enzymes. According to certain aspects of this disclosure, the preferential release of tricaprylin in the intestine and / or colon rather than the stomach may increase the bioavailability of tricaprylin, given the location of lipid digestive enzymes in these regions.

[0046]

[0062] In certain aspects of this disclosure, the pharmaceutical composition provides preferential release of a high drug load of tricaprine in the user's lower gastrointestinal tract. Without intending to be bound by theory, preferential release of tricaprine in the lower gastrointestinal tract, including the colon, may provide a reduction in nausea and associated adverse events compared to a standard dose of unformulated MCT oil. Furthermore, improved bioavailability of tricaprine can generally result in increased in vivo ketone body production compared to a standard dose of unformulated MCT oil.

[0047]

[0063] In certain embodiments, the pharmaceutical composition may contain high drug loads of tricaprline, such as at least about 20% of the total composition, at least about 25% of the total composition, at least about 30% by weight of the total composition, at least about 40% by weight of the total composition, about 30% to about 65% by weight of the total composition, about 30% to about 60% by weight of the total composition, about 40% to about 50% by weight of the total composition, or about 40% to about 45% by weight of the total composition.

[0048]

[0064] In certain aspects, the pharmaceutical compositions of this disclosure comprise one or more emulsion-forming excipients. In certain embodiments, the one or more emulsion-forming excipients may be any emulsifier capable of forming an emulsion with MCT oil. Examples include lecithin (e.g., Phospholipon 90G), hydrogenated castor oil including polyoxyl 40 castor oil (e.g., Kolliphor RH40), caprylic acid esters, sodium oleate, glycerol, citrate esters of monoglycerides and diglycerides (e.g., Citrem), monoglycerides and diglycerides of fatty acids including propylene glycol monocaprylate (e.g., Capmul PG-8), and combinations thereof. The emulsion-forming excipient may be present in an amount sufficient to provide the desired emulsion formation. For example, in certain embodiments, the emulsion-forming excipient may be present in an amount such as about 1% to about 10%, about 1.3% to about 10%, etc., of the weight of the total composition.

[0049]

[0065] In certain embodiments, the emulsion-forming excipient may include a combination of lecithin, Kallichore RH40, and a caprylic acid ester emulsifier. In other embodiments, the emulsion-forming excipient may include a combination of lecithin, sodium oleate, and glycerol. In yet another embodiment, the emulsion-forming excipient may include Citrem alone or in combination with fatty acid monoglycerides and diglycerides.

[0050]

[0066] In one embodiment, the pharmaceutical composition of this disclosure is administered orally. The therapeutically effective dose of tricaprine may be any amount or dose sufficient to produce the desired effect, and may in part depend on the severity and stage of the condition, the size and condition of the patient, and other factors readily apparent to those skilled in the art. The dose may be given as a single dose or as several doses, divided over a course of several weeks, for example, as discussed elsewhere in this specification.

[0051]

[0067] In certain aspects, the Disclosure relates to a method for treating a disease or disorder related to cognitive decline in a subject requiring treatment for such a disease or disorder, comprising the step of administering to the subject an amount of the pharmaceutical composition of the Disclosure effective in increasing the ketone body concentration in the subject, thereby treating the disease or disorder. In certain embodiments, the pharmaceutical composition of the Disclosure may be administered separately from the context of a ketogenic diet. For example, in the context of the Disclosure, carbohydrates may be consumed concurrently with the pharmaceutical composition disclosed herein.

[0052]

[0068] In accordance with certain aspects of this disclosure, diseases and disorders associated with cognitive decline include age-related memory impairment (AAMI), Alzheimer's disease (AD), Parkinson's disease, Friedreich's ataxia (FRDA), GLUT1 deficiency epilepsy, fairy palsy, and Rabson-Mendenhall syndrome, coronary artery bypass graft (CABG) dementia, anesthesia-induced amnesia, Huntington's disease, and many others.

[0053]

[0069] In another aspect, patients have or are at risk of developing disease-related cognitive decline caused by impaired neuronal metabolism, such as cognitive decline associated with Alzheimer's disease (AD), Parkinson's disease, Friedreich's ataxia (FRDA), GLUT1 deficiency epilepsy, fairy palsy, and Rabson-Mendenhall syndrome, coronary artery bypass graft (CABG) dementia, anesthesia-induced amnesia, Huntington's disease, and many others.

[0054]

[0070] In another embodiment, the subject lacks the ApoE4 genotype as described in U.S. Patent No. 8,445,535, which is incorporated herein by reference in whole.

[0071] As used herein, decreased neuronal metabolism refers to all possible mechanisms that may lead to decreased neuronal metabolism. Such mechanisms include, but are not limited to, mitochondrial dysfunction, free radical attack, reactive oxygen species (ROS) generation, ROS-induced neuronal apoptosis, defective glucose transport or glycolysis, membrane ion potential imbalance, and dysfunction in calcium efflux.

[0055]

[0072] According to the present invention, high blood ketone levels provide an energy source to brain cells with impaired glucose metabolism, leading to improved cognitive function. As used herein, “subject” and “patient” refer interchangeably to any mammal, including humans, that can benefit from the treatment of diseases and conditions associated with or resulting from impaired neuronal metabolism.

[0056]

[0073] "Effective dose" refers to the amount of a compound, substance, or pharmaceutical composition described herein that is effective in achieving a particular biological outcome. The effectiveness of treatment for the aforementioned conditions may be determined by improvement in the results of at least one neuropsychological test. These neuropsychological tests are known in the art and include, among others, the Clinical Global Impression of Change (CGIC), the Ray Auditory Language Learning Test (RAVLT), the First-Last Names Association Test (FLN), the Telephone Dialing Test (TDT), the Memory Assessment Clinics Self-Rating Scale (MAC-S), Symbol Digit Coding (SDC), the SDC Delayed Recall Task (DRT), the Distributive Attention Test (DAT), Visual Sequence Comparison (VSC), DAT Dual Task, the Mini-Mental State Examination (MMSE), and the Geriatric Depression Rating Scale (GDS).

[0057]

[0074] The term “cognitive function” refers to special, normal, or appropriate physiological activity of the brain, including, without limitation, at least one of the following: mental stability, memory / recall ability, problem-solving ability, reasoning ability, thinking ability, judgment ability, learning, perception, intuition, attention, and self-awareness. “Enhancement of cognitive function” or “improvement of cognitive function” refers to any improvement in special, normal, or appropriate physiological activity of the brain, including, without limitation, at least one of the following: mental stability, memory / recall ability, problem-solving ability, reasoning ability, thinking ability, judgment ability, learning, perception, intuition, attention, and self-awareness, as measured by any means appropriate in the art. “Decline of cognitive function” or “impairment of cognitive function” refers to any decline in special, normal, or appropriate physiological activity of the brain.

[0058]

[0075] 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 allele of the apolipoprotein E gene is determined. Non-E4 carriers were found to perform better than those with the E4 allele when an increase in ketone body levels was induced by MCT. Furthermore, those with the E4 allele had higher fasting ketone body levels, and these levels continued to rise at 2-hour time intervals. Therefore, E4 carriers may require medication to increase their higher ketone levels or their ability to utilize existing ketone bodies.

[0059]

[0076] In one embodiment, the pharmaceutical composition of this disclosure is administered orally. The therapeutically effective dose of the therapeutic agent may be any amount or dose sufficient to produce the desired effect, and may in part depend on the severity and stage of the condition, the size and condition of the patient, and other factors readily apparent to those skilled in the art. The dose may be given as a single dose or as several doses, divided over a course of several weeks, for example, as discussed elsewhere in this specification.

[0060]

[0077] In one embodiment, the pharmaceutical compositions of this disclosure are administered in a dose required to increase blood ketone bodies to a level required to treat and / or prevent any disease or age-related cognitive decline, such as AD or AAMI. An appropriate dose can be determined by those skilled in the art.

[0061]

[0078] In one embodiment, oral administration of the pharmaceutical composition of this disclosure results in hyperketonemia. In one embodiment, hyperketonemia leads to the utilization of ketone bodies as energy in the brain, even in the presence of glucose. In addition, hyperketonemia results in a substantial (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 has been reported to reduce cognitive dysfunction associated with systemic hypoglycemia in normal humans (Veneman, T. et al., Effect of hyperketonemia and hyperlactic acidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans, Diabetes, 1994, 43:1311~7). It should be noted that systemic hypoglycemia is different from local defects in glucose metabolism that occur in any disease such as AD, AAMI, or age-related cognitive decline.

[0062]

[0079] Dosage may be as needed or desired, for example, once a month, once a week, daily, or more than once a day. Similarly, dosing may be every other day, every week, every month, every three days, every three weeks, every three months, every four days, every four weeks, or every four months, etc. Dosing may be multiple times per day. When used as a supplement to normal nutritional requirements, the composition may be administered directly to the patient or otherwise come into contact with or be mixed with daily feed or food.

[0063]

[0080] The pharmaceutical compositions provided herein are, in one embodiment, intended for “long-term” consumption, which may be referred to herein as “extended” periods. “Long-term” administration, as used herein, generally refers to periods exceeding one month. Periods longer than two, three, or four months constitute one embodiment of the present invention. Embodiments also include longer-term periods, including periods longer than five, six, seven, eight, nine, or ten months. Periods exceeding eleven months or one year are also included. Longer-term use, extending to one, two, or three years or more, is also conceivable herein. “Regular,” as used herein, refers to the administration or consumption of the composition at least weekly. More frequent administration or consumption, such as two or three times a week, is included. Regimen including consumption at least once a day are also included. Those skilled in the art will recognize that the blood levels of ketone bodies or specific ketone bodies achieved can be a useful measure of administration frequency. Any frequency that allows for the maintenance of blood levels of the measured compound within an acceptable range, whether or not it is expressly illustrated herein, may be considered useful herein. Those skilled in the art will recognize that the frequency of administration is related to the composition being consumed or administered, and that some compositions may require more or less frequent administration to maintain the desired blood levels of the compound being measured (e.g., ketone bodies).

[0064]

[0081] Administration may be performed regularly, for example, as part of a treatment regimen in a patient. A treatment regimen may include causing the patient to regularly take an amount of the pharmaceutical composition of this disclosure that is effective in enhancing cognitive function, memory, and behavior in the patient. Regular intake may be daily or weekly, once a day, or two, three, four or more times a day. Similarly, regular administration may be every day or every week, every three days or every three weeks, every four days or every four weeks, every five days or every five weeks, or every six days or every six weeks, and in such a regimen, administration may be multiple times a day. The goal of regular administration is to provide the patient with an optimal dose of the pharmaceutical composition of this disclosure, as illustrated herein.

[0065]

[0082] For example, the dosage of the compositions of the present invention, including those containing MCT, may be administered in an effective amount to increase cognitive abilities in patients suffering from diseases of decreased neuronal metabolism, such as any disease including AD, AAMI, or age-related cognitive decline.

[0066]

[0083] The effective dose of a compound capable of increasing MCT, i.e., ketone body concentration, to an amount effective in treating or preventing a disease, condition, or disorder (e.g., cognitive loss caused by decreased neuronal metabolism) will be apparent to those skilled in the art. As stated herein above, such an effective dose may be determined based on the disclosed blood ketone levels. When the compound capable of increasing ketone body concentration is an MCT, the MCT dose is, in one embodiment, in the range of about 0.05 g / kg / day to about 10 g / kg / day of MCT. In another embodiment, the dose is in the range of about 0.25 g / kg / day to about 5 g / kg / day of MCT. In another embodiment, the dose is in the range of about 0.5 g / kg / day to about 2 g / kg / day of MCT. In yet another embodiment, the dose is in the range of about 0.1 g / kg / day to about 2 g / kg / day. In other embodiments, the MCT dose may be at least 5g / day, at least 10g / day, at least 15g / day, at least 20g / day, at least 25g / day, at least 30g / day, at least 35g / day, at least 40g / day, at least 45g / day, at least 50g / day, at least 55g / day, at least 60g / day, at least 65g / day, at least 70g / day, at least 75g / day, at least 80g / day, etc. In yet another embodiment, the MCT dose may be 10g / day to 80g / day, 20g / day to 80g / day, 30g / day to 80g / day, 30g / day to 60g / day, etc.

[0067]

[0084] In some embodiments, to mitigate potential safety and tolerability issues associated with high doses, the final dose of the MCT may be achieved by escalating to the final therapeutically effective dose. For example, the escalation may be carried out over 1 to 8 weeks, 1 to 6 weeks, 1 to 4 weeks, 2 to 4 weeks, etc., by adjusting the dose of tricaprline by 1 g to 20 g, 2 g to 20 g, 5 g to 20 g, 5 g to 10 g per week.

[0068]

[0085] Convenient unit-dose containers and / or compositions include, among other things, sachets or containers of spray-dried particles, tablets, capsules, lozenges, troches, hard candies, nutrition bars, nutrition drinks, metered-dose sprays, creams, and suppositories. Compositions may be combined with pharmaceutically acceptable excipients such as gelatin, oils, and / or other pharmaceutically active agents. Some examples of compositions are described in WIPO Publication 2008 / 170235, which is incorporated in whole by reference. For example, compositions may be advantageously combined with and / or used in combination with other therapeutic or prophylactic agents different from the compound. In many cases, administration in combination with the composition enhances the efficacy of such agents. For example, the compound may be advantageously used in combination with antioxidants, compounds that enhance the efficiency of glucose utilization, and mixtures thereof.

[0069]

[0086] In some embodiments, the compounds of the present invention may be administered in the substantial absence of protein, or may be co-formulated without protein.

[0087] In some embodiments, the MCT preparation may be co-administered with a protein, or may be co-formulated with a protein.

[0070]

[0088] In some embodiments, the MCT formulation may be co-administered with a protein or co-formulated with a protein. The protein may consist of more than one type of protein or one or more different proteins from different sources. Suitable proteins are known in the art. When co-formulated, the amount of protein used may include at least about 0.1 g, at least about 1 g, at least about 10 g, at least about 50 g, at least about 100 g, at least about 150 g, at least about 200 g, at least about 250 g, at least about 300 g, or at least about 400 g. The amount of protein may be at least about 1 g, at least about 50 g, or at least about 100 g. The composition may contain about 15% to about 40% protein on a dry weight basis. Sources of such protein include legumes, cereals, dairy products, nuts, seeds, fruits, vegetables, animals, insects, synthetic sources (e.g., genetically modified yeast), or mixtures thereof. The composition optionally also includes other protein-containing components such as dried whey and other dairy products or by-products. In some embodiments, the MCT preparation is administered in the presence of a protein-based drink (e.g., Ensure and similar protein-based drinks and nutritional supplements).

[0071]

[0089] In addition, in some embodiments, the MCT formulation may be co-administered with carbohydrates or co-formulated with carbohydrates. The carbohydrate may contain more than one type of carbohydrate. Suitable carbohydrates include monosaccharides such as glucose, fructose, and sucrose from conventional sources known in the art, such as corn syrup and sugar beet. When co-formulated, the amount of carbohydrate used may be 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, or at least about 400g. The amount of carnitine may be at least about 1g, at least about 50g, or at least about 100g. The composition may contain about 15% to about 40% carbohydrates on a dry weight basis. Such sources of carbohydrates include grains or cereals such as rice, maize, sorghum, alfalfa, barley, soybeans, canola, oats, wheat, or mixtures thereof. The composition may also optionally include other carbohydrate-containing ingredients such as dried whey and other dairy products or by-products. [Examples]

[0072]

[0090] The following embodiments are included to demonstrate preferred embodiments of the present invention. Those skilled in the art should recognize that the techniques disclosed in the following embodiments represent techniques that the inventors have found to work well in practice of the present invention and can therefore be considered to constitute a preferred mode for that practice. However, those skilled in the art should recognize that many modifications may be made in light of this disclosure to the particular embodiments disclosed, and similar or equivalent results can still be obtained without departing from the spirit and scope of the present invention.

[0073] Example 1 - Rat model for formulation development

[0091] Background: To rapidly screen tricapriline formulations, rats were investigated as a pharmacokinetic (PK) model for human formulations. PK studies are conducted to evaluate absorption, distribution, metabolism, and elimination (ADME) in animals. PK results allow the inventors to define dose, dosage frequency, route of administration, and action.

[0074]

[0092] Methods: Several formulations of tricaprylin were studied in human PK studies, and the release of C from the formulations was investigated. max , T max We also found several differences in AUC (described herein and shown in Figure 1).

[0075]

[0093] In this study, the PK profiles of these same formulations were investigated in rats to determine whether rats could qualitatively replicate human results. Healthy young adult male Sprague Dawley rats were used as the test system for this PK study. Five animals were used per group, the animals were 9–12 weeks old, and the weight variation of the animals did not exceed ±20% of the mean weight.

[0076]

[0094] The drugs were administered to animals by forced oral administration at the Biological Resource Centre (BRC), Agency for Science, Technology and Research (A*STAR), and Singapore. Sample analysis was performed by Agilex Biolabs Pty Ltd (Thebarton SA, Australia). The concentrations of acetoacetate and β-hydroxybutyrate in rat serum were determined by LC / MS. Ketone body concentration (μM) was calculated as the sum of acetoacetate (μM) and β-hydroxybutyrate (μM) concentrations. Ketone body data were analyzed using WinNonlin.

[0077]

[0095] Results: The rats qualitatively reflected the results from the human studies. Formulations that showed slow release in humans were similarly found to have slow release in SD rats. Formulations that showed fast release in humans were also found to have fast release in SD rats. The results of the rat studies are shown in Figure 2 and Table 1 below.

[0078] [Table 1]

[0079]

[0096] Conclusion: In this preliminary study, rats represent a model for the development of tricaprylin formulations.

[0080] Example 2 - PK-PD Modeling and Simulation Experiment

[0097] Background: This embodiment was designed to determine which dose is expected to yield the best results based on optimally filling a “metabolic gap” identified in the brains of Alzheimer’s disease (AD) subjects using dual-tracer (FDG-acetoacetate) PET imaging. This metabolic gap represents the gap in energy consumption between healthy young brain cells and AD brain cells. “Filling the gap” correlates with improved cognitive function.

[0081]

[0098] Methods: Using advanced analytical and pharmacological modeling, we developed a PK-PD model that fitted available data, including brain metabolic rate data from MCT intake. After model development, simulated experiments were performed to determine the dose required to fill 25–50% of the metabolic gap.

[0082]

[0099] Results: More than 20g of caprylic acid triglyceride is required to "fill the gap." The inventors' goal is to fill 25-50% of the metabolic gap to ensure clinical efficacy. Referring to Figure 3, the target dose is 60g of tricapryline per day.

[0083] Example 3 - PK study of an optimized formulation of tricaprylin

[0100] Part 1:

[0101] A phase 1, randomized, single-center, single-dose, placebo-controlled, three-way crossover study to compare the pharmacokinetics, safety, and tolerability of lipid multiparticle (LMP) and spray-dried (SD) formulations of tricaprylin (TC) for ketone body production.

[0084]

[0102] the purpose:

[0103] Main purpose:

[0104] To determine the safety and tolerability of single-dose administration of two tricaprine formulations (AC-SD-03 and AC-LMP-01) and a placebo formulation (AC-SD-03P) in healthy male volunteers.

[0085]

[0105] To compare ketone body levels (i.e., total ketones, β-hydroxybutyrate [BHB], acetoacetate [AcAc]), tricaprylin, and octanoic acid levels after single-dose administration of the tricaprylin formulations AC-SD-03 and AC-LMP-01, and the placebo formulation AC-SD-03P, in healthy young male volunteers.

[0086]

[0106] Secondary / exploratory objectives

[0107] To determine the effects of APOE4 status on tricaprylin BA, metabolism, and ketone body production.

[0087]

[0108] Methodology:

[0109] This was an open-label, randomized, three-way crossover, pilot pharmacokinetic (PK), safety, and tolerability study to assess safety and tolerability in healthy male volunteers under feeding conditions, comparing ketone body levels (i.e., total ketones, BHB, AcAc), tricaprylin, and octanoic acid levels after single-dose administration of each of the tricaprylin formulations, AC-SD-03 and AC-LMP-01, and the placebo formulation AC SD-03P, and to determine the effect of APOE4 status on tricaprylin BA, metabolism, and ketone body production.

[0088]

[0110] One of two cohorts consisted of 12 healthy adult men. I registered to receive medication there. • Cohort 1: Includes Chinese subjects (n=6) • Cohort 2: Includes subjects from non-Chinese (Caucasian) ethnic groups (n=6)

[0111] Both cohorts were studied simultaneously. On day 1 of period 1, participants were randomized to one of six treatment sequences.

[0089]

[0112] On day 1 of periods 1, 2, and 3, 30 minutes after the completion of breakfast, subjects received a single oral dose of AC-SD-03, AC-LMP-01, and AC-SD-03P. Subjects received each treatment at one time. Blood samples were collected before and up to 24 hours after administration for PK sampling to measure total ketones, BHB, AcAc, octanoic acid, and tricaprylin. Prior to participating in the trial, subjects had a screening visit to determine eligibility within 28 days prior to day 1 of period 1. Upon arrival for restraint, subjects were randomized to receive a single dose of either the study drug (AC-SD-03 and AC-LMP-01) or placebo (AC-SD-03P) (1:1:1 active drug vs. placebo) according to a randomization scheme developed by Syneos. There was a two-day rest period between doses. Participants were included from day -1 of period 1 to 24 hours after blood collection on day 1 of period 3, as indicated by the Clinical Research Unit (CRU). The total study period (excluding screening but including a 3-day follow-up period) was 11 days.

[0090]

[0113] Diagnostic and key criteria for inclusion:

[0114] Participants had to be healthy, non-smoking males / adults aged 18–50 years (inclusive) with a body mass index (BMI) ≥ 18.0 and < 32.0 kg / m2. All participants had to adhere to the inclusion and exclusion criteria outlined in the protocol and were deemed eligible for enrollment in this study based on medical and medication history, demographic data (including sex, age, race, ethnicity, weight [kg], height [cm], and BMI [kg / m2]), vital signs measurements, 12-lead electrocardiogram (ECG), physical examination, urinary drug screening, alcohol breath test, and clinical laboratory tests (serological chemistry, blood tests, urinalysis, human immunodeficiency virus [HIV], hepatitis C [HCV] antibodies, and hepatitis B surface antigen [HBSAg], hepatitis B core antigen [HCsAg], thyroid-stimulating hormone (TSH), and hemoglobin A1c tests).

[0091]

[0115] Treatment protocol: The following formulations were administered using the following treatment regimen.

[0092] [Table 2]

[0093] [Table 3]

[0094]

[0116] Blood sample collection points: A total of 13 blood samples were obtained from each subject for PK analysis of ketone body levels (i.e., total ketones, BHB, AcAc), tricaprylin, and octanoic acid during each period. Blood samples were collected at -1 hour, 0 hours (before drug administration), and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12, and 24 hours after drug administration.

[0095]

[0117] Criteria for evaluation:

[0118] Safety:

[0119] Adverse events (TEAE) occurring under treatment, serious adverse events (SAE), test parameters (serum chemistry, blood tests, and urine tests), 12-lead ECG, physical examinations including body weight, gastrointestinal side effects, and vital sign determination.

[0096]

[0120] Pharmacokinetics:

[0121] Using the standard non-compartmental method, the following PK parameters could be calculated for ketone body levels (i.e., total ketone, BHB, AcAc), tricaprylin levels, and octanoic acid levels (unadjusted and baseline-adjusted): AUC 0-t , AUC 0-4 , AUC 0-6 , AUC 0-8 , AUC 0-24 , AUC 0-inf , AUC %extrap , T max , K el , t 1 / 2 and C max .

[0097]

[0122] Parametric ANOVA (linear mixed model) and geometric confidence intervals for treatment comparisons A / B, A / C, and B / C for AUC 0-t , AUC 0-4 , AUC 0-6 , AUC 0-8 , AUC 0-24 , AUC 0-inf (if calculated), and C max for unadjusted and baseline-adjusted data;

[0123] Factors in the ANOVA model: sequence, subjects within sequence, period, and treatment;

[0124] Ln-transformed parameters: AUC 0-t , AUC 0-4 , AUC 0-6 , AUC 0-8 , AUC 0-24 , AUC 0-inf (if calculated), and C max .

[0098]

[0125] Statistical methods:

[0126] Safety analysis:

[0127] Demographic parameters were summarized descriptively. Demographic and baseline characteristics (including sex, age, race, ethnicity, smoking history, height, weight, and BMI) were summarized for each randomized treatment sequence and overall.

[0099]

[0128] Using the Medical Dictionary for Regulatory Activities (MedDRA) version 22.0, all AEs reported during the study were classified by organ-specific major categories (SOCs) and primary terms (PTs).

[0100]

[0129] TEAEs were summarized for each actual treatment. The number and percentage of subjects experiencing an AE, as well as the number of TEAEs, are shown in the table. Subjects who experienced the same AE (in terms of MedDRA basic terminology) more than once were counted only once for that event, but the total number of events was also counted for each category. This also applies to the subcategories shown in the summary.

[0101]

[0130] The relationship of each TEAE was classified according to the research protocol as potentially related to the investigational drug, possibly, possibly, unlikely, or not related. The severity of the TEAE was classified as mild, moderate, or severe according to the research protocol.

[0102]

[0131] The following summary was presented. • Overall summary of TEAE • TEAE by SOC and PT TEAE based on SOC, PT, and severity. TEAE based on the relationship between SOC, PT, and the investigational drug. • Severe TEAEs due to SOC and PT

[0132] Laboratory data (blood tests and serum chemistry) were compiled for each scheduled visit according to the protocol, for each actual procedure performed. Actual values ​​and actual changes from baseline were presented.

[0103]

[0133] In addition, a shift schedule was presented showing the change in the category of the examination range results (low, normal, high) from the baseline to each post-baseline visit.

[0134] The evaluation of urine test results was summarized using a frequency table for each planned protocol time point and for each actual procedure.

[0104]

[0135] Vital sign measurements were compiled for each planned time point in the protocol, for each actual procedure. Actual values ​​and actual changes from baseline are presented.

[0136] ECG values ​​were compiled for each scheduled visit according to the protocol, for each actual procedure. Actual values ​​and actual changes from baseline were presented. In addition, a shift table showing the change in ECG result categories (normal, clinically insignificant abnormality, or clinically significant abnormality) from baseline to each post-baseline visit was presented.

[0105]

[0137] The results of the pain numerical rating scale and the Baxter Retching Faces Scale were summarized for each scheduled visit / time in each protocol, with mean scores for each actual treatment. Actual values ​​and actual changes from baseline are presented.

[0106]

[0138] Pharmacokinetic analysis:

[0139] Individual concentration-versus-time curves were presented using a linear scale for each analyte classified by treatment. Average concentration-versus-time curves were also presented for each analyte classified by treatment, using both a linear and semi-logarithmic scale.

[0107]

[0140] Unadjusted and baseline-adjusted PK concentrations of total ketones, BHB, AcAc, tricaprylin, and octanoic acid were listed and summarized for nominal sample collection time and cohort / actual treatment. Descriptive statistics (arithmetic and geometric mean, standard deviation [SD], arithmetic and geometric coefficient of variation [CV%], minimum [Min], maximum [Max], and median) for ketone body levels (i.e., total ketones, BHB, AcAc), tricaprylin, and octanoic acid concentrations against time, as well as PK parameters categorized by treatment, are also presented.

[0108]

[0141] result

[0142] Pharmacokinetics:

[0143] Refer to Figure 4 for mean (±SD) plasma total ketone concentrations. Generally, ketone body levels (AUC total ketones, BHB, AcAc) were comparable (or, in some cases, higher) for treatment A (AC-SD-03) compared to treatment B (AC-LMP-01). Ketone body levels were significantly higher for treatments A (AC-SD-03) and B (AC-LMP-01) compared to treatment C (AC-SD-03P), which was a placebo.

[0109]

[0144] Refer to Figure 5, showing mean (±SD) unadjusted total ketone plasma concentration, linear scale, overall. As shown, Pre-1: "1 hour before breakfast"; Pre-: "0 hours before medication"; Treatment A: AC-SD-03, dose to deliver 20 g of tricaprine, approximately 50 g dose equivalent to 20 g of tricaprine; Treatment B: AC-LMP-01, dose to deliver 20 g of tricaprine, approximately 50 g dose equivalent to 20 g of tricaprine; and Treatment C: AC-SD-03P, placebo corresponding to AC-SD-03, approximately 50 g.

[0110]

[0145] Mean unadjusted total ketone C for AC-SD-03 (Treatment A) and AC-LMP-01 (Treatment B) maxThe overall concentrations were 1043.6 μM (CV% 39.2) and 632.0 μM (CV% 70.5), respectively, but for treatment C (AC-SD-03P) it was 258.7 μM (CV% 38.0). Based on these results, we can conclude that treatments A and B showed concentrations exceeding 500 μM, and therefore confirmed the ketone body production status of AC-SD-03 and AC-LMP-01. Overall, T max The median values ​​for treatments A, B, and C were approximately 1.5 hours, 3.4 hours, and 4.0 hours after medication administration, respectively.

[0111]

[0146] Following administration of AC-SD-03 20g (Treatment A), higher variability in PK parameters was observed in Cohort 1 (Chinese population) (CV% 50-60%) compared to Cohort 2 (Caucasian population) (CV% 18-20%) for total ketones, BHB, and tricaprylin. Alternative analysis, excluding subject 037 which showed outlier results in ketone body levels, showed reduced variability in Cohort 1, which had the effect of reducing the difference between the two populations for total ketone levels (CV% 40%). However, the main underlying cause of these results obtained for subject 037 was not clearly identified.

[0112]

[0147] Refer to Figure 6, which shows mean (±SD) unadjusted tricaprine plasma concentrations, linear scale, overall. As shown, Pre-1: "1 hour before breakfast"; Pre-: "0 hours before medication"; Treatment A: AC-SD-03, dose to deliver 20 g of tricaprine, approximately 50 g dose equivalent to 20 g of tricaprine; Treatment B: AC-LMP-01, dose to deliver 20 g of tricaprine, approximately 50 g dose equivalent to 20 g of tricaprine; and Treatment C: AC-SD-03P, placebo corresponding to AC-SD-03, approximately 50 g.

[0113]

[0148] The rate and extent of tricaprylin absorption were significantly greater after a single oral dose of AC-SD-03 20g (Treatment A) compared with AC-LMP-01 20g (Treatment B) (3 to 6 times greater in each case). 1 / 2elThe duration for treatment A was 2.4 hours, and for treatment B it was 2.1 hours. max The median value was present around 2.5 hours after treatment A and around 4 hours after medication administration for treatment B (overall population).

[0114]

[0149] Refer to Figure 7, showing mean (±SD) unadjusted octanoic acid plasma concentrations, linear scale, overall. As shown, Pre-1: "1 hour before breakfast"; Pre-: "0 hours before medication"; Treatment A: AC-SD-03, dose to deliver 20 g of tricaprine, approximately 50 g equivalent to 20 g of tricaprine; Treatment B: AC-LMP-01, dose to deliver 20 g of tricaprine, approximately 50 g equivalent to 20 g of tricaprine; and Treatment C: AC-SD-03P, placebo corresponding to AC-SD-03, approximately 50 g.

[0115]

[0150] Regarding octanoic acid levels, the concentration was below the limit of quantification in all 11 of the 12 subjects enrolled in the study, making comparison between the two test treatments, AC-SD-03 20g (Treatment A) and AC-LMP-01 20g (Treatment B), and the placebo formulation AC-SD-03P (Treatment C), impossible.

[0116]

[0151] Since all subjects were APOE4 negative, the effect of apolipoprotein E4 (APOE4) status on tricaprylin bioavailability, metabolism, and ketone body production could not be determined in this study.

[0117]

[0152] Safety and tolerability:

[0153] Referring to the table below, a total of nine TEAEs were reported by 8 out of 12 subjects (safety analysis population) who received at least one dose of the study drug (66.7%). Overall, the frequency of TEAE reporting was at least seven times higher in subjects receiving treatment A (58.3%) compared to treatment B (8.3%). No TEAEs were reported by subjects after receiving treatment C (placebo). The frequency of TEAE reporting was similar across all treatments between Chinese and Caucasian subjects. The most frequently reported TEAE was nausea, reported in 5 subjects after receiving treatment A (3 Caucasian and 2 Chinese subjects). All reported TEAEs were mild in severity and considered to be related to the investigational drug. There were no deaths during the study, and none of the reported TEAEs were severe or serious. TEAEs did not lead to discontinuation of treatment by subjects after administration.

[0118] [Table 4]

[0119]

[0154] There were no TEAEs associated with clinical laboratory results, vital signs, and ECG results. No relevant differences were observed between treatment groups or between Chinese and Caucasian subjects in the mean and baseline changes for clinical laboratory results, vital signs, and ECG results.

[0120]

[0155] Most participants had a pain numerical rating scale (NRS) score of 0 during the study. A few participants had a pain NRS score of 1–3 within 3 hours after administration of treatment A or B. Most participants had a Baxter nausea facial expression (BARF) score of ≤4 during the study. BARF scores of 1 or higher were mostly reported within 2 hours after administration of treatment A. There were no relevant differences in pain NRS and BARF scores between Chinese and Caucasian participants.

[0121]

[0156] Conclusion:

[0157] Safety:

[0158] Overall, both the tricaprylin formulations (AC-SD-03 and AC-LMP-01) and the placebo formulation were well tolerated in healthy male volunteers, with no major safety concerns and only expected mild GI symptoms, when administered as a single dose equivalent to 20 g of tricaprylin or as safflower oil without dose escalation. No GI adverse events were reported with the placebo formulation (AC-SD-03P, Treatment C), which contained the same excipients as Treatment A (AC-SD-03) but with tricaprylin replaced by safflower oil.

[0122]

[0159] Pharmacokinetics:

[0160] A single dose of the AC-SD-03 formulation (containing 20 g of tricaprylin) in 12 healthy volunteers resulted in a low tricaprylin concentration (1 μM) peaking at 2.5 hours, while the degradation product and the first absorbed compound, octanoic acid, peaked at approximately 500 μM after 1 hour. This indicates that T max 1.5 hours and 1 mM C max This resulted in a ketone body response with a BHB to AcAc ratio of approximately 3.5:1. 1 / 2el The incubation period was 2.4 hours, and ketone levels returned to baseline levels after 4 hours.

[0123]

[0161] There were no statistically significant differences between the Caucasian and Chinese populations. The AC-LMP-01 formulation (containing 20 g of tricaprylin) had a similar total ketone AUC overall to AC-SD-03. 0-inf However, a lower C max (632 μM) and longer T max It had a slower release profile, with a release time of 3.4 hours. Alternative analyses (excluding subject 037) reinforced the above conclusions. The placebo formulation AC-SD-03P was not ketone-producing.

[0124]

[0162] Part 2:

[0163] A phase 1, randomized, single-center, single-dose, placebo-controlled, three-way crossover study to compare the pharmacokinetics, safety, and tolerability of lipid multiparticle (LMP) and spray-dried (SD) formulations of tricapriline (TC) for ketone body production. Part 2 includes a two-way crossover to compare the pharmacokinetics, safety, and tolerability of two spray-dried (SD) formulations of tricapriline (TC) for ketone body production.

[0125]

[0164] the purpose:

[0165] To determine the safety and tolerability of each single-dose tricaprine preparation (AC-SD-03, manufactured by Anthem Bioscience Pvt. Ltd., India, and AC-1202) in healthy male volunteers.

[0126]

[0166] To compare ketone body levels (i.e., total ketones, β-hydroxybutyrate [BHB], acetoacetate [AcAc]), tricaprylin, and octanoic acid levels after single-dose administration of the tricaprylin preparations AC-SD-03 (Anthem) and AC-1202, respectively, in healthy young male volunteers.

[0127]

[0167] Methodology:

[0168] Following the completion of Part 1, we prepared an addendum to the protocol to include a two-way crossover study (referred to as Part 2) to compare the pharmacokinetics (PK), safety, and tolerability of two spray-dried (SD) formulations of tricaprylin for ketone body production.

[0128]

[0169] These are the main changes between Part 1 and Part 2 of this study. • The subjects received two formulations of the investigational product in Part 2; • The AC-SD-03 formulation used in Part 2 was manufactured at a different manufacturing site than the AC-SD-03 formulation used in Part 1; • 12-lead electrocardiogram (ECG) and safety examination analysis were performed only during the screening visit in Part 2; • The status of the target apolipoprotein E gene 4 (APOE4) was not determined in Part 2; • Gastrointestinal adverse events were not measured in Part 2 using the Numerical Rating Scale (NRS) and the Baxter Nausea Facial Expression (BARF) scale.

[0129]

[0170] We were able to enroll 20(20) healthy adult male subjects (Chinese and non-Chinese) in Part 2. These could be the same subjects who participated in Part 1, or they could be new subjects. • Cohort 1: Chinese subjects (minimum of 10 subjects specified) • Cohort 2: Non-Chinese ethnic group origin

[0171] To maximize the number of Chinese subjects included in the study, we were able to enroll additional Chinese subjects in Cohort 1 instead of those in Cohort 2.

[0130]

[0172] On day 1 of period 1, subjects were randomized to one of two treatment sequences. On day 1 of periods 1 and 2, after completion of the protocol-specified standard breakfast, subjects received a single oral dose of either AC-SD-03 or AC-1202. Subjects received each treatment at one time. Blood samples were collected before administration and up to 8 hours after administration for PK sampling to measure total ketones, BHB, acetoacetate, octanoic acid, and tricaprylin.

[0131]

[0173] There was a two-day break between doses. The total study period (excluding screening but including a three-day follow-up period) was eight days.

[0174] Aside from the changes mentioned above, there were no changes in the study implementation regarding research procedures, safety monitoring, restraints, and follow-up compared to Part 1.

[0132]

[0175] Diagnostic and key criteria for inclusion:

[0176] The target group is individuals with a Body Mass Index (BMI) of ≥18.0 and <32.0 kg / m². 2 Applicants had to be healthy males / adult non-smokers aged 18-50 years (inclusive) with the following characteristics: [details omitted]. There were no changes to the selection criteria between Part 1 and Part 2.

[0133]

[0177] Treatment protocol: The following formulations were administered using the following treatment regimen.

[0134] [Table 5]

[0135] [Table 6]

[0136]

[0178] Criteria for evaluation

[0179] Safety and tolerability:

[0180] Safety was monitored through vital sign measurements, clinical tests, adverse events (AEs), and physical examinations.

[0137]

[0181] Pharmacokinetics:

[0182] The following main PK parameters were calculated for total ketones, BHB, acetoacetate, octanoic acid, and tricaprylin: AUC0-t, AUC0-4, C max , and T max Where appropriate, AUC0-inf, AUC%Extrap, Kel, and T1 / 2 were calculated.

[0138]

[0183] PK parameters were obtained from concentrations using non-compartmental analysis with actual time.

[0184] Descriptive statistics (arithmetic and geometric mean, standard deviation [SD], coefficient of variation [CV%], minimum [Min], maximum [Max], and median) are presented for total ketone, BHB, acetoacetate, octanoic acid, and tricaprylin concentrations as well as PK parameters over time.

[0139]

[0185] In the statistical analysis system (SAS), using the generalized linear model (GLM) method, analysis of variance (ANOVA) is performed unadjusted and appropriately baseline-adjusted, with natural logarithm (ln) transformed AUC0-t, AUC0-4, AUC0-inf (if calculated), and C max This was performed at an alpha level of 0.05.

[0140]

[0186] The ratio of the geometric mean (A / B) and the 90% confidence interval of the ratio of the geometric mean based on the least squares mean from the ANOVA of the ln-transformed data are given as AUC0-t, AUC0-4, AUC0-inf (if calculated), and C. max We calculated the following.

[0141]

[0187] Statistical methods:

[0188] There were no changes to the analysis plan between Part 1 and Part 2.

[0189] result

[0190] Safety and tolerability:

[0191] Refer to the table below. A total of 28 TEAEs were reported by 17 (81.0%) of the 21 subjects who received at least one dose of the study drug. Eleven subjects (52.4%) reported TEAEs after receiving AC-SD-03 (treatment D), and 12 subjects (60.0%) reported TEAEs after receiving AC-1202 (treatment E). The frequency of subjects reporting TEAEs was lower in Caucasians than in Chinese subjects for both treatments.

[0142] [Table 7]

[0143]

[0192] All of the most frequently reported TEAEs in this study were associated with SOC gastrointestinal disorders. The most frequently reported TEAEs were abdominal distension, abdominal discomfort, and nausea. Gastrointestinal AEs are expected with the use of tricaprylin.

[0144]

[0193] The most frequently reported TEAE was abdominal distension, reported in 5 subjects (23.8%) after receiving AC-SD-03 (2 Chinese and 3 Caucasian subjects) and in 8 subjects (40.0%) after receiving AC-1202 (5 Chinese and 3 Caucasian subjects). All reported TEAEs were mild in severity and considered related to the investigational drug. There were no deaths, and none of the reported TEAEs were severe or critical. None of the TEAEs led to discontinuation of treatment after administration.

[0145]

[0194] There were no TEAEs related to vital signs, and no relevant differences were observed between treatments or between Chinese and Caucasian subjects.

[0195] Pharmacokinetics:

[0196] Refer to Figure 8 to show mean unadjusted PK concentration, total, and total ketones (μM) (PK population). As shown, -1Pre: "1 hour before breakfast"; Pre: "0 hours before medication"; Treatment D: AC-SD-03; Treatment E: AC-1202. AUC and C max Based on this, ketone body levels (total ketones, BHB, AcAc) were generally higher after administration of AC-1202 than after administration of AC-SD-03. In fact, the maximum concentrations achieved were statistically higher for AC-1202 than for AC-SD-03 for total ketones [AC-1202: 1111.56 μM (CV% 28.79) vs. AC-SD-03: 917.32 μM (CV% 32.44), p=0.001] (Figure 8), for BHB [AC-1202: 822.34 μM (CV% 28.72) vs. AC-SD-03: 675.69 μM (CV% 32.73), p=0.001), and for AcAc [AC-1202: 292.26 μM (CV% 33.24) vs. AC-SD-03: 241.41 μM (CV% 33.74), p=0.008]. Although statistically different, administration of AC-SD-03 or AC-1202 resulted in ketone body concentrations exceeding 500 μM, thus confirming the ketone-producing state of both formulations.

[0146]

[0197] Conversely, the body level of tricaprylin is Cmax As measured, the levels were statistically significantly lower after administration of AC-1202 than after administration of AC-SD-03 [AC-1202: 478.90 ng / mL (CV% 57.14) vs. AC-SD-03: 940.80 ng / mL (CV% 54.16), p<0.0001] (Figure 9). Refer to Figure 9 to show mean unadjusted PK concentrations, overall, and total tricaprylin (ng / mL) (PK population). As shown, -1Pre: "1 hour before breakfast"; Pre: "0 hours before administration"; Treatment D: AC-SD-03; Treatment E: AC-1202.

[0147]

[0198] The level of octanoic acid, the first compound absorbed, was also higher after administration of AC-1202 than after administration of AC-SD-03 (Figure 10). Refer to Figure 10, which shows the mean unadjusted PK concentration, overall, and total octanoic acid (μM) (PK population). As shown, -1Pre: "1 hour before breakfast"; Pre: "0 hours before administration"; Treatment D: AC-SD-03; Treatment E: AC-1202. The maximum concentration reached was statistically higher with AC-1202 than with AC-SD-03 [AC-1202: 604.18 μM (CV% 31.47) vs. AC-SD-03: 528.91 μM (CV% 31.38), p=0.046].

[0148]

[0199] Time to reach maximum total ketone and BHB concentrations (T max There was no difference between the two formulations in the median time (1.5 hours for both). However, T max For AcAc (AC-1202: 1.734 hours vs. AC-SD-03: 1.5 hours), tricaprylin (AC-1202: 2.5 hours vs. AC-SD-03: 2.25 hours), and octanoic acid (AC-1202: 1.5 hours vs. AC-SD-03: 1.0 hours), it took slightly longer to reach the desired time using AC-1202 than using AC-SD-03.

[0149]

[0200] AUC and C maxRegarding AC-SD-03, the total ketone levels measured after administration were approximately 0.9 and 0.8 times the levels measured after administration of AC-1202, respectively. Based on point estimates D / E of 82%–92%, ketone body levels (AUC total ketones, BHB, AcAc) were comparable for AC-SD-03 and AC-1202. On the other hand, AUC and C max Tricaprylin levels for these substances were approximately 1.7 and 2.0 times higher after AC-SD-03 administration compared to AC-1202 administration, respectively. The ratios measured for BHB, AcAc, and octanoic acid were similar to those measured for total ketones.

[0150]

[0201] C max Variability in AUC was similar between the two formulations for total ketones, BHB, AcAc, tricaprylin, and octanoic acid. Variability was generally higher for tricaprylin than for the other analytes in both formulations.

[0151]

[0202] Differences in PK of each analyte were also analyzed for each cohort. Levels of total ketones, BHB, AcAc, tricaprylin, and octanoic acid were C max And measured by AUC, when the AC-SD-03 formulation was administered, the results were generally higher in the Chinese population than in the Caucasian population. max It took a little longer to reach the target. After administration of the AC-1202 formulation, the levels of total ketones, BHB, AcAc, and octanoic acid were C max And measured by AUC, it was higher in the Chinese population than in the Caucasian population, but T max The same was true (longer T in Chinese than in Caucasians). max (Except for AcAc, which appears to have the same properties). Overall levels of tricaprylin, measured by AUC, were generally higher in the Chinese population than in the Caucasian population, but lower in the CUC population. max We reached our destination.

[0152]

[0203] When the AC-SD-03 formulation was administered, the variability of PK parameters was higher in Caucasian subjects than in Chinese subjects for total ketones, BHB, and AcAc. There was no significant difference in the variability of PK parameters for octanoic acid. The PK parameters measured for tricaprylin after administration of this formulation were highly variable. max The variation in AUC was 36% among Chinese compared to 71% among Caucasians, and the variation in AUC was 57% among Chinese compared to 34-43% among Caucasians.

[0153]

[0204] When the AC-1202 formulation was administered, there were no significant differences in the variation of PK parameters between Chinese and Caucasian subjects for total ketones, BHB, AcAc, tricaprylin, and octanoic acid. max The variability was generally higher for tricapriline than for other analytes in this formulation (Chinese: 63%, Caucasian: 50%). Furthermore, for tricapriline, the variability in AUC was significantly higher in Caucasians (60%) than in Chinese (25%).

[0154]

[0205] Conclusion:

[0206] These results indicate that both tricaprlin formulations (AC-SD-03 and AC-1202) were well tolerated in healthy male volunteers, with no major safety concerns, apart from expected mild gastrointestinal side effects.

[0155]

[0207] Total ketone production, a definitive pharmacodynamic marker for tricapriline, increased with AC-1202 compared to AC-SD-03. Exposure levels were numerically higher in Chinese men than in Caucasian men, but inter-individual variability within each cohort prevents a final conclusion that metabolic differences exist between these ethnic groups.

[0156]

[0208] Example 4 - PK study in healthy elderly subjects

[0209] A Phase 1, single-center, multi-dose, open-label study to determine the safety, tolerability, and pharmacokinetics of the AC-SD-03 formulation of tricapriline in healthy elderly volunteers.

[0210] the purpose:

[0211] Main purpose

[0212] To determine the safety and tolerability of multiple doses of tricaprlin, formulated as AC-SD-03, administered using an escalation scheme in healthy elderly volunteers.

[0157]

[0213] Secondary purpose

[0214] To determine ketone body levels (total ketones, β-hydroxybutyrate [βHB], acetoacetate [AcAc]) after administration of multiple doses of AC-SD-03 in healthy elderly volunteers.

[0158]

[0215] Evaluation criteria:

[0216] Key evaluation criteria

[0217] Safety and tolerability outcomes were based on electrocardiogram (ECG) reports, gastrointestinal (GI) scales, vital sign measurements, laboratory tests, adverse event (AE) reports, and physical examinations.

[0159]

[0218] AE and GI scales are presented in tables, and summary statistics for ECG, vital signs, and clinical laboratory safety studies may have been calculated and provided where deemed clinically appropriate.

[0160]

[0219] Secondary outcome items

[0220] Pharmacokinetic (PK) parameters (C max , T max AUC0-4, AUC4-8, AUC0-8, and AUC0-24) were calculated for total ketones, βHB, and AcAc for PK sample collection over 24 hours on day 27. max and T max The total ketones, βHB, and AcAc for PK sample collection on days 15 and 21 were calculated.

[0161]

[0221] Exploratory evaluation items

[0222] The potential effects of AC-SD-03 on hepatic outcomes were based on FibroScan reports and the aspartate aminotransferase (AST):alanine aminotransferase (ALT) ratio.

[0162]

[0223] Methodology:

[0224] This was an open-label, multi-dose study to evaluate the safety, tolerability, and limited pharmacokinetics of AC-SD-03 after dose escalation to 75 g twice daily (30 g twice daily tricaprylin). The population for this study consisted of 12 healthy elderly men and women aged 50 years or older.

[0163]

[0225] After a screening period of up to 28 days, eligible subjects arrived at the Clinical Research Unit (CRU) for check-in on day 1. On day 1, subjects underwent pre-administration plasma serum samples for PK. Dose 1 (12.5g) of AC-SD-03 was administered 30 minutes after completion of a standard breakfast. Dose 2 was administered 30 minutes after completion of a standard lunch.

[0164]

[0226] With the goal of reaching a dose of 75g twice daily, the subjects were able to gradually increase their dose according to an escalation scheme.

[0165] [Table 8]

[0166]

[0227] If a subject failed to reach the target dose of 75 g twice daily over the four-week period, the subject would have been reduced to the next best-to-accepted dose and continued at that dose. At the discretion of the principal investigator, a second attempt at dose escalation may have been made once symptoms subsided. After the second unsuccessful attempt, the subject continued the remainder of the study at the best-to-accepted dose. However, the subject tolerated the planned dose escalation, and the subject's regimen was not modified for tolerability.

[0167]

[0228] Participants were scheduled to be confined from day 1 to day 28, but were released early due to the Covid-19 pandemic. Therefore, final PK samples were obtained early, and the results at the end of the study were summarized for clinical tests, vital signs, and ECGs where applicable. On days 15 and 21, participants collected plasma samples before and after administration (1, 1.5, and 2 hours) for PK. On day 24, participants collected a plasma sample before administration for PK. After the first dose on day 24, PK samples were collected 24 hours later to measure ketone body levels (βHB, AcAc). Checkout was on day 25 after completion of the scheduled assessment. Participants who discontinued the study early may have been replaced by the sponsor's selection.

[0168]

[0229] A total of 12 participants were enrolled in the study. Eleven participants completed the procedure according to the protocol but withdrew when the study was interrupted on day 25 due to the disruption caused by Covid-19, and one participant withdrew on day 23. All 12 participants were included in the safety and PK analyses. All participants enrolled in this study were determined by the principal investigator to be normal, healthy volunteers who met all inclusion criteria and none of the exclusion criteria.

[0169]

[0230] The test product was AC-SD-03 (reconstituted tricaprylin oral powder), lot number A222000035. AC-SD-03 was weighed, mixed with 240 mL of water, shaken using a medication container (with lid), and administered orally. Immediately after administration, the remaining solution in the container was rinsed with 60 mL of water, and the total of approximately 300 mL of medication solution consumed per dose was administered to the subjects. The total duration of participation, including the screening period, was approximately 60 days for each subject.

[0170]

[0231] Criteria for evaluation:

[0232] Pharmacokinetics:

[0233] PK parameters (C max , T max , AUC0-4, AUC4-8, AUC0-8, and AUC0-24) were evaluated for total ketone, βHB, and AcAc calculated for PK samples collected over the 24 hours on day 24. C max and T max were calculated for total ketone, βHB, and AcAc for PK samples collected on days 15 and 21.

[0171]

[0234] Safety:

[0235] Safety was evaluated based on 12-lead ECG reports, GI scales, vital sign measurements, clinical laboratory tests, AE reports, and physical examinations.

[0172]

[0236] Statistical methods:

[0237] Pharmacokinetics:

[0238] Plasma concentrations of βHB, AcAc, and total ketone were tabulated and summarized for all subjects in the PK population for each study day and time point. Mean and individual concentration-time profiles for days 15, 21, and 24 were presented on linear and semi-logarithmic scales. Linear mean plots were presented with and without SD. PK parameters for plasma βHB, AcAc, and total ketone were tabulated and summarized for all subjects in the PK population for each study day and dose. Inferential statistics were not performed on the PK data.

[0173]

[0239] Safety:

[0240] Inferential statistics were not performed on the safety data. Applicable continuous variables were summarized using sample size (n), arithmetic mean (mean), standard deviation (SD), minimum, median, and maximum. Where appropriate, frequencies and percentages were reported for categorical data.

[0174]

[0241] Results

[0242] Safety and tolerability:

[0243] There were no deaths, serious adverse events (SAEs), or discontinuation of subjects due to AEs reported in the study. The AC-SD-03 formulation was well tolerated, and all subjects were able to escalate to the maximum dose of 30 g tricaprylin BID. Refer to the table below; the most common AEs were primarily gastrointestinal, mild, resolving, and occurring mainly at the maximum dose.

[0175] [Table 9]

[0176]

[0244] Overall, a total of 32 TEAEs were reported by 8 subjects (67%) in the study, and no trend in AE incidence was observed in relation to AC-SD-03 dose levels. Gastrointestinal AEs were frequently reported in the study (67% of subjects). The most common GI events included constipation, epigastric pain, and nausea. Overall, the majority of AEs reported in the study were of mild severity and were considered at least possibly related to the investigational drug. All AEs resolved by the completion of the study. The majority of BARF and pain NRS scores were 0, indicating no pain or abdominal discomfort. Mild pain and / or discomfort was occasionally reported, and the majority of events were reported at doses of 37.5 g or higher of AC-SD-03. No treatment-related trends were observed in vital signs, laboratory results (including ALT / AST ratio), physical examination assessments, FibroScan, or safety ECG data in this study.

[0177]

[0245] Pharmacokinetics:

[0246] The following table summarizes the PK parameters for plasma βHB, AcAc, and total ketones: Summary of unadjusted pharmacokinetic parameters of plasma βHB after a 4-week dose escalation to AC-SD-03 (30g twice daily tricaprylin) at 75g twice daily (PK population)

[0178] [Table 10]

[0179] Summary of unadjusted pharmacokinetic parameters of plasma AcAc after a 4-week dose escalation to 75g twice daily AC-SD-03 (30g twice daily tricaprylin) (PK population)

[0180] [Table 11]

[0181] Summary of unadjusted pharmacokinetic parameters of total plasma ketones after a 4-week dose escalation to AC-SD-03 (30g twice daily tricaprylin) at 75g twice daily (PK population)

[0182] [Table 12]

[0183]

[0247] Following escalation to 75g twice daily AC-SD-03 (30g tricaprylin), the peak concentrations of surrogate PK markers βHB, AcAc, and total ketones (Figure 11) were observed approximately 1–1.5 hours after administration on days 15 and 21. On day 24, if both administration opportunities were obtained during the sampling period, the peak concentration was observed approximately 1.5 hours after administration of the second dose. As expected, βHB was the most abundant. Refer to Figure 11 to see the mean plasma total ketone concentrations over the escalation periods of day 15 / 15g BID, day 21 / 20g BID, and day 24 / 30g BID.

[0184]

[0248] After gradually increasing the dosage from day 15 (15g tricaprylin) to day 24 (30g tricaprylin), the geometric mean C of βHB, AcAc, and total ketones was measured. max These increased by 2.9 times, 2.3 times, and 2.7 times, respectively. On day 24, the total exposure after the first dose (AUC0-4) was similar to that after the second dose (AUC4-8) based on a similar time interval.

[0185]

[0249] The concentration after the first dose on that day did not return to the baseline level before the second dose on that day was administered. The likelihood of endogenous ketosis occurring during the inter-meal time frame was low; thus, the concentration level was likely due to the administration of tricaprilin. After the second dose, the concentration returned to the baseline level by approximately 12 hours.

[0186]

[0250] Conclusion:

[0251] During the titration period, the T of the PK markers βHB, AcAc, and total ketones max was observed at approximately 1 - 1.5 hours after dosing on days 15 and 21. After titration to the maximum dose of 75 g twice daily on day 24, the T max was 1.5 hours after the second dose.

[0187]

[0252] After titration from day 15 (15 g of tricaprilin) to day 24 (30 g of tricaprilin), the geometric mean C of βHB, AcAc, and total ketones max increased 2.9-fold, 2.3-fold, and 2.7-fold, respectively. On day 24, the overall exposure (AUC0-4) after the first dose was similar to that after the second dose (AUC4-8) based on the same time interval. After the second dose, the concentration returned to the baseline level by 12 hours.

[0188]

[0253] Based on visual determination of the curve, ketosis (as defined by levels of total ketones exceeding 300 μM) was present for most of the daytime hours (up to 12 hours after the first meal of the day).

[0189]

[0254] Multiple-dose administration of tricaprilin formulated as AC-SD-03, administered using a titration scheme with doses ranging from 12.5 g to 75 g of AC-SD-03 (5 g to 30 g of tricaprilin), appeared to be generally safe and was well tolerated in the healthy elderly volunteers in this study. All subjects completed the titration schedule up to the maximum dose, and the side effects were generally mild in severity and mostly GI-related.

[0190] Example 5 - Ethnic analysis of safety and tolerability

[0255] This study investigates the pharmacokinetics, safety, and tolerability of tricapril in healthy young Caucasian and Asian male volunteers to understand and clarify any differences between the two populations and to identify any ethnic susceptibility. In this study, data from several studies were analyzed to assess any ethnic differences in the safety and tolerability of tricapril. The studies analyzed included Caucasian and Asian (Chinese) subjects, and some analyses were performed to compare effects between Caucasians and Asians. Ethnic Chinese participants were defined as having all four grandparents being Chinese. Total ketone levels were quantified using a valid LC-MS / MS bioanalysis assay.

[0191]

[0256] Methods: Study 1 was a food effects study of a spray-dried tricaprine formulation (AC-SD-01) conducted in healthy young men. Study 2 was a two-part study conducted in healthy young male volunteers, testing a prototype slow-release spray-dried tricaprine formulation (AC-SD-03); an initial formulation of tricaprine (AC-1202); and a placebo against AC-SD-03. Both of these studies included Caucasian and Asian (Chinese) subjects, and several analyses were performed to compare the effects between Caucasians and Chinese. To explore whether ethnicity influences total ketone body exposure after tricaprine administration, the pharmacokinetic parameter AUC was analyzed from Study 2. 0-t and C max We investigated and classified individuals according to their ethnicity (Chinese or Caucasian).

[0192]

[0257] Results: Pharmacokinetic differences between ethnic groups in each study were slight and not very apparent after adjusting for body weight. Combining data from Part 2 of Study 2, the mean total ketones in Chinese participants were max The average total ketone AUC was 965 μM for Caucasian participants and 1000 μM for Chinese participants (p=0.78), while the average total ketone AUC for Chinese participants was 965 μM. 0-tThe average AUC0-t was 3011 h*uM, but for Caucasian participants, it was 2953 h*uM (p=0.89). (See Figures 12A-12B.) No differences were observed in the AE profile between Asian and Caucasian subjects. Mild to moderate spontaneously resolving GI adverse events (bloating, nausea, abdominal discomfort) were observed in all studies. Furthermore, based on a literature review, there are no known differences between Caucasians and Chinese in processes involved in the absorption, metabolism, distribution, and excretion of medium-chain triglycerides (MCTs), or in the oxidation of medium-chain fatty acids to ketone bodies.

[0193]

[0258] Conclusion: Exposure to total ketones, the active species, after administration of tricaprylin is sufficient for healthy whites. Compared to humans, healthy ethnic Chinese participants showed no differences. There appear to be no ethnic differences in the absorption or metabolism of ketone-producing tricaprylin, or in their safety and tolerability profiles. Non-limitingly, the present invention includes the following embodiments. [Aspect 1] A method of administering tricapriline to a person in need for the treatment of a disease or disorder, The step of administering a pharmaceutical composition containing a therapeutically effective amount of tricaprine to a subject in need thereof, wherein the therapeutically effective amount of tricaprine is at least 300 μmol / L of the maximum serum concentration of total ketones (C max ) Provided, A method wherein the therapeutically effective dose of tricaprine is 30g to 80g per day, administered as a single dose or in divided doses. [Aspect 2] The therapeutically effective dose of tricaprylin is at least 500 ng / mL of tricaprylin C max The method according to embodiment 1, which provides... [Aspect 3] The therapeutically effective dose of tricaprlin reaches the maximum serum concentration of total ketones (C) at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours after administration. maxThe method according to embodiment 1, which provides ). [Aspect 4] Total ketones C max The method according to embodiment 1, wherein the concentration is at least 500 μmol / L, at least 750 μmol / L, or at least 1000 μmol / L. [Aspect 5] The method according to embodiment 1, wherein the subject requiring it is an elderly subject. [Aspect 6] The method according to embodiment 5, wherein the aged subject lacks the ApoE4 genotype. [Aspect 7] The therapeutically effective dose of tricaprylin is at least 400 μmol / L, at least 450 μmol / L, or at least 500 μmol / L of β-hydroxybutyrate (BHB). max The method according to embodiment 1, which provides... [Aspect 8] The therapeutically effective dose of tricaprylin is at least 50 μ mol / L, at least 60 μ mol / L, at least 70 μ mol / L, at least 80 μ mol / L, at least 90 μ mol / L, or at least 100 μ C of acetoacetic acid (AcAc) at mol / L max The method according to embodiment 1, which provides... [Aspect 9] The method according to embodiment 1, wherein the disease or disorder is a disease or disorder related to cognitive decline. [Aspect 10] The method according to embodiment 9, wherein the disease or disorder associated with the decline in cognitive function is selected from Alzheimer's disease and age-related memory impairment. [Aspect 11] The method according to embodiment 1, wherein the pharmaceutical composition is formed as an emulsion for administration. [Aspect 12] The therapeutic effective dose of tricaprine is 30g to 80g per day, up to the final therapeutic effective dose. Dose adjustment The method according to embodiment 1, which is achieved by doing so. [Aspect 13] The aforementioned Dose adjustment The method according to embodiment 12, wherein the administration of tricaprin is carried out over a period of 2 to 4 weeks by adjusting the dosage of 5 g to 10 g per week. [Aspect 14] The pharmaceutical composition is used to determine total ketones C after administration of tricapriline. max Ethnicity in exposure levels The method according to embodiment 1, wherein the administration is carried out in such a way that no effect is observed in Caucasian versus Asian subjects.

Claims

1. A pharmaceutical composition comprising tricaprylin for use in a method for treating a disease or disorder related to cognitive decline in a subject requiring treatment for a disease or disorder related to cognitive decline, The method comprises the step of administering a therapeutically effective dose of tricaprine to the subject in need thereof, The therapeutically effective dose of tricaprylin is at least 300 μmol / L of the maximum serum concentration of total ketones (C ｍａｘ ) Provided by; The therapeutically effective dose of tricaprin is 30 g to 80 g per day, administered as a single or divided dose; The therapeutically effective dose of tricaprline is achieved by adjusting the dose up to the final therapeutically effective dose, and this dose adjustment is carried out over 2 to 4 weeks by adjusting the dose of tricaprline by 5 g to 10 g per week. The aforementioned pharmaceutical composition.

2. The therapeutically effective dose of tricaprylin is at least 500 ng / mL of tricaprylin C ｍａｘ The pharmaceutical composition according to claim 1, which provides the following:

3. The therapeutically effective dose of tricaprlin reaches the maximum serum concentration of total ketones (C) at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours after administration. ｍａｘ The pharmaceutical composition according to claim 1, which provides ).

4. Total ketones C ｍａｘ The pharmaceutical composition according to claim 1, wherein the concentration is at least 500 μmol / L, at least 750 μmol / L, or at least 1000 μmol / L.

5. The pharmaceutical composition according to claim 1, wherein the subject requiring it is an elderly subject.

6. The pharmaceutical composition according to claim 5, wherein the elderly subject lacks the ApoE4 genotype.

7. The therapeutically effective dose of tricaprylin is at least 400 μmol / L, at least 450 μmol / L, or at least 500 μmol / L of β-hydroxybutyrate (BHB). ｍａｘ The pharmaceutical composition according to claim 1, which provides the following:

8. The therapeutically effective dose of tricaprylin 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 of acetoacetate (AcAc). ｍａｘ The pharmaceutical composition according to claim 1, which provides the following:

9. The pharmaceutical composition according to claim 1, wherein the disease or disorder associated with the decline in cognitive function is selected from Alzheimer's disease and age-related memory impairment.

10. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is formed as an emulsion for administration.

11. The aforementioned pharmaceutical composition is used to determine total ketone C after administration of tricapriline. ｍａｘ The pharmaceutical composition according to claim 1, administered in such a manner that the influence of ethnicity on exposure levels is not observed in Caucasians versus Asians.

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