Stable liquid pharmaceutical compositions with high drug loading of medium chain triglycerides and related methods

Abstract

The present invention relates to high drug-loaded compositions of medium chain triglycerides (MCTs) and methods of treatment with such compositions in amounts effective to elevate ketone body levels to treat conditions involving neuronal hypometabolism, such as Alzheimer's disease.

Description

[Technical field]

[0001] FIELD OF THE DISCLOSURE

[0001] This disclosure relates to liquid pharmaceutical compositions containing high drug loadings of medium chain triglycerides, and methods of making and using such compositions. [Background technology]

[0002]

[0002] Medium chain triglycerides (MCTs) consist of fatty acids with chain lengths of 5 to 12 carbons. MCTs have been widely studied and have known nutritional and medicinal uses. MCTs have a melting point and are liquid at room temperature. Furthermore, MCTs are relatively small, and when hydrolyzed, the fatty acids formed from MCTs are ionizable at physiological pH and therefore largely soluble in aqueous solutions.

[0003]

[0003] When intended for use as a pharmaceutical composition, it is often desirable to prepare compositions of active ingredients in preservative-free liquid dosage forms that are ready to use at room temperature. However, long-term stability, both physicochemical and microbiological, is extremely difficult to achieve. Summary of the Invention [Problem to be solved by the invention]

[0004]

[0004] Therefore, there is a need in the art for ready-to-use, preservative-free liquid dosage compositions of MCTs, particularly those that have sufficient long-term stability and at active ingredient to excipient levels (referred to herein as drug loading) that are sufficiently high for pharmaceutical use. [Means for solving the problem]

[0005]

[0005] In one aspect, the present disclosure relates to a liquid pharmaceutical composition comprising caprylic triglyceride in at least about 30% by weight of the total composition, and one or more emulsion forming excipients present in a concentration sufficient to form a stable emulsion for at least one month at ambient conditions. In some aspects, the caprylic triglyceride is present in an amount of about 30% to about 60% by weight of the total composition. In some aspects, the purity of the caprylic triglyceride is at least 95%.

[0006]

[0006] In some aspects, the one or more emulsion-forming excipients are selected from the group consisting of lecithin (e.g., Phospholipon 90G), hydrogenated castor oil including polyoxyl 40 castor oil (e.g., Kolliphor RH40), caprylic acid esters, sodium oleate, glycerol, citric acid esters of mono- and diglycerides (e.g., Citrem), mono- and diglycerides of fatty acids including propylene glycol monocaprylate (e.g., Capmul PG-8), and combinations thereof.

[0007] In some aspects, the one or more emulsion-forming excipients are selected from the group consisting of lecithin, Kolliphor RH40, caprylic acid ester emulsifiers, and combinations thereof. In some aspects, the one or more emulsion-forming excipients are selected from the group consisting of lecithin, sodium oleate, glycerol, and combinations thereof. In some aspects, the one or more emulsion-forming excipients are selected from the group consisting of Citrem, mono- and diglycerides of fatty acids, and combinations thereof.

[0008]

[0008] In some aspects, one or more emulsion-forming excipients are present in an amount of about 1% to about 10% by weight of the total composition, preferably about 1% to about 8% by weight of the total composition.

[0009] In some aspects, at least two emulsion-forming excipients are present in the composition, and at least one of the emulsion-forming excipients is present in an amount of at least 2.0% by weight of the total composition. In some aspects, the at least two emulsion-forming excipients are present in a 1:1 to 2:1 ratio relative to each other.

[0010] In some aspects, the liquid pharmaceutical compositions of the present disclosure form emulsions that are stable for at least about one month at ambient conditions. In some aspects, the stable emulsions exhibit an average particle size of less than 0.5 μm for at least one month at ambient conditions, preferably less than 0.3 μm for at least one month at ambient conditions, preferably less than 0.2 μm for at least one month at ambient conditions. In other aspects, the emulsions may have an average particle size of less than about 1000 nm but greater than about 100 nm, e.g., from about 100 nm to 500 nm, from about 200 nm to about 300 nm, from about 160 nm to about 190 nm, etc.

[0011]

[0011] In some aspects, the liquid pharmaceutical composition of the present disclosure further comprises an oil-soluble flavoring agent.

[0012] In yet another aspect, the present disclosure relates to a method of treating a disease or disorder associated with cognitive decline in a subject in need thereof, comprising administering to the subject a liquid pharmaceutical composition of the present disclosure in an amount effective to increase a ketone body level in said subject, thereby treating said disease or disorder. In certain embodiments, the disease or disorder associated with cognitive decline is selected from Alzheimer's disease and age-associated memory impairment.

[0012]

[0013] While multiple aspects are disclosed, still other aspects of the present disclosure will become apparent to those skilled in the art from the following detailed description, which shows and describes specific aspects of the present disclosure. When realized, the present invention is capable of modification in various aspects, all without departing from the spirit and scope of the present disclosure. Thus, the detailed description should be regarded as illustrative in nature and not restrictive. [Brief description of the drawings]

[0013] [Figure 1]

[0014] FIG. 1 illustrates an exemplary method for the preparation of a liquid pharmaceutical composition of the present disclosure. [Diagram 2]

[0015] FIG. 1 shows exemplary ingredients, concentrations, and compositions of liquid pharmaceutical compositions according to aspects of the present disclosure. [Diagram 3]

[0016] FIG. 3 shows a compositional region of optimized performance for the liquid pharmaceutical composition of FIG. 2 according to an embodiment of the present disclosure. [Figure 4]

[0017] FIG. 3 illustrates the performance of the composition of the liquid pharmaceutical composition of FIG. 2 according to an embodiment of the present disclosure. [Diagram 5]

[0018] FIG. 3 illustrates the performance of the composition of the liquid pharmaceutical composition of FIG. 2 according to an embodiment of the present disclosure. [Figure 6]

[0019] FIG. 3 illustrates the performance of the composition of the liquid pharmaceutical composition of FIG. 2 according to an embodiment of the present disclosure. [Figure 7]

[0020] FIG. 1 shows exemplary particle size distributions for various Citrem formulations according to aspects of the present disclosure. [Figure 8]

[0021] FIG. 1 illustrates stability results of oleic acid formulations according to aspects of the present disclosure. [Figure 9]

[0022] FIG. 1 illustrates visual stability results of oleic acid formulations according to aspects of the present disclosure. [Figure 10]

[0023] FIG. 1 illustrates stability results of oleic acid formulations according to aspects of the present disclosure. [Figure 11]

[0024] FIG. 1 illustrates stability results of oleic acid formulations according to aspects of the present disclosure. [Figure 12]

[0025] FIG. 1 illustrates visual stability results of oleic acid formulations according to aspects of the present disclosure. [Figure 13]

[0026] FIG. 1 illustrates stability results of oleic acid formulations according to aspects of the present disclosure. [Figure 14]

[0027] FIG. 1 illustrates stability results of oleic acid formulations according to aspects of the present disclosure. [Figure 15]

[0028] FIG. 1 illustrates visual stability results of oleic acid formulations according to aspects of the present disclosure. [Figure 16]

[0029] FIG. 1 illustrates stability results of oleic acid formulations according to aspects of the present disclosure. [Figure 17]

[0030] FIG. 1 illustrates stability results of oleic acid formulations according to aspects of the present disclosure. [Figure 18]

[0031] FIG. 1 illustrates visual stability results of oleic acid formulations according to aspects of the present disclosure. [Figure 19]

[0032] FIG. 1 illustrates stability results of oleic acid formulations according to aspects of the present disclosure. [Figure 20]

[0033] FIG. 1 shows exemplary particle size distributions for various formulations of gamma irradiated vs. retained samples according to an embodiment of the present disclosure. [Figure 21A]

[0034] 21A-21J show exemplary particle size distributions of a lead formulation over time according to an embodiment of the present disclosure. [Figure 21B] 21A-21J show exemplary particle size distributions of a lead formulation over time according to an embodiment of the present disclosure. [Figure 21C] 21A-21J show exemplary particle size distributions of a lead formulation over time according to an embodiment of the present disclosure. [Figure 21D] 21A-21J show exemplary particle size distributions of a lead formulation over time according to an embodiment of the present disclosure. [Figure 21E] 21A-21J show exemplary particle size distributions of a lead formulation over time according to an embodiment of the present disclosure. [Figure 21F] 21A-21J show exemplary particle size distributions of a lead formulation over time according to an embodiment of the present disclosure. [Figure 21G]21A-21J show exemplary particle size distributions of a lead formulation over time according to an embodiment of the present disclosure. [Fig. 21H] 21A-21J show exemplary particle size distributions of a lead formulation over time according to an embodiment of the present disclosure. [Figure 21I] 21A-21J show exemplary particle size distributions of a lead formulation over time according to an embodiment of the present disclosure. [Figure 21J] 21A-21J show exemplary particle size distributions of a lead formulation over time according to an embodiment of the present disclosure. [Figure 22A]

[0035] FIG. 1 shows pharmacokinetic parameters including total ketone Cmax. [Figure 22B] FIG. 1 shows total ketone AUC for a lead formulation according to an embodiment of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014]

[0036] By way of background, medium-chain triglycerides ("MCTs") are metabolized differently than the more common long-chain triglycerides (LCTs). In particular, when compared to LCTs, MCTs are readily digested to release medium-chain fatty acids (MCFAs), which exhibit increased portal vein absorption and undergo obligate oxidation. The small size and reduced hydrophobicity of MCTs increase the rate of digestion and absorption compared to LCTs. When MCTs are ingested, they are first processed by lipases that cleave the fatty acid chains from the glycerol backbone. Several lipases in the preduodenum preferentially hydrolyze MCTs over LCTs, and the released MCFAs are then partially absorbed directly by the gastric mucosa. MCFAs that are not absorbed in the stomach are absorbed directly into the portal vein and are not packaged into lipoproteins. Because blood transport is much more rapid than lymph, MCFAs arrive quickly in the liver, where they undergo obligate oxidation.

[0015]

[0037] In contrast, long-chain fatty acids (LCFAs) derived from normal dietary fats are re-esterified to LCTs and packaged into chylomicrons for transport to lymph. This significantly slows the metabolism of LCTs compared to MCTs. Upon feeding, LCFAs undergo little oxidation in the liver, mainly due to the inhibitory effect of malonyl-CoA. When conditions favor fat storage, malonyl-CoA is produced as an intermediate in lipogenesis. Malonyl-CoA allosterically inhibits carnitine palmitoyltransferase I, thereby inhibiting LCFA transport into mitochondria. This feedback mechanism prevents a futile cycle of lipolysis and lipogenesis.

[0016]

[0038] MCFAs are largely immune to the regulations that control the oxidation of LCFAs. MCFAs enter mitochondria without the use of carnitine palmitoyltransferase I, and therefore MCFAs bypass this regulatory step and are oxidized regardless of the metabolic state of the organism. Importantly, because MCFAs enter the liver rapidly and are readily oxidized, large amounts of ketone bodies are readily produced from MCFAs. Thus, large oral doses of MCTs (e.g., about 20 mL to 40 mL) can result in sustained hyperketonemia.

[0017]

[0039] The present disclosure generally relates to a liquid pharmaceutical composition that comprises high loading amount of at least one MCT, and the method of making and using such composition.In certain embodiments, the liquid pharmaceutical composition forms a stable liquid emulsion when administered in an aqueous use environment, for example in water or in an aqueous use environment.In certain embodiments, the MCT is caprylic triglyceride as described herein.

[0018]

[0040] In certain embodiments, the liquid pharmaceutical formulation may be "preservative-free." In such embodiments, the formulation may form a stable liquid emulsion that maintains sterility (i.e., sufficient bioburden reduction to permit pharmaceutical use) for at least 1 month, at least 2 months, at least 3 months, at least 6 months, or at least 12 months at ambient conditions without the use of preservatives.

[0019]

[0041] In certain aspects, the pharmaceutical composition of the present disclosure is a liquid pharmaceutical composition that includes high drug loading of MCT, such as caprylic triglyceride, and one or more emulsion-forming excipients present at sufficient concentration to form an emulsion at ambient conditions.The pharmaceutical composition may include the amounts of ingredients described herein.In some embodiments, the composition may form a stable liquid emulsion at ambient conditions, for example, for at least 1 day, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, etc.The emulsion of the present disclosure may generally be formed by high shear mixing or "high pressure homogenization" as understood in the art.

[0020]

[0042] As described herein, the pharmaceutical compositions of the present disclosure can form stable liquid emulsions at ambient conditions. An emulsion refers to a composition that, when diluted with water or other aqueous medium and gently mixed, results in a stable oil / water emulsion that has an average particle size of less than about 1 μm but greater than about 100 nm (i.e., 0.1-1 μm) and is generally polydisperse. Such emulsions are stable, meaning that there is no visible phase separation and no visible crystallization.

[0021]

[0043] In some aspects, the pharmaceutical compositions of the present disclosure form emulsions that are stable at ambient conditions for at least about 1 month. In some aspects, the stable emulsions exhibit an average particle size of less than 0.5 μm at ambient conditions for at least 1 month, preferably less than 0.3 μm at ambient conditions for at least 1 month, preferably less than 0.2 μm at ambient conditions for at least 1 month. In other aspects, the emulsions may have an average particle size of less than about 1000 nm but greater than about 100 nm, e.g., from about 100 nm to 500 nm, from about 200 nm to about 300 nm, from about 160 nm to about 190 nm, etc.

[0022]

[0044] As discussed above, the pharmaceutical compositions of the present disclosure form stable emulsions when administered in an aqueous use environment, e.g., water, a pharma- ceutical suitable aqueous solution, or in vivo. By way of example, the emulsions may be stable at ambient conditions for at least about 24 hours, at least 1 day, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, etc. In certain embodiments, the emulsions formed do not phase separate while stable. In certain embodiments, the emulsions may have an average particle size of less than about 1 μm but greater than about 100 nm (i.e., 0.1-1 μm).

[0023]

[0045] In certain embodiments, the emulsion formed may be stable at gastric pH, e.g., a pH of about 1 to about 3, about 1.2 to about 2.9, etc. In certain embodiments, the emulsion formed may be stable at intestinal and / or colonic pH, e.g., a pH of about 5 to about 7, about 5.5 to about 6.9, etc. In certain embodiments, the emulsion formed may begin to degrade or phase separate after about ½ to about 1 hour at gastric pH, but does not release the encapsulated MCT until intestinal or colonic pH. Without being limited by theory in this regard, in vitro digestion assays indicate that the encapsulated MCT is released from the emulsion at intestinal and / or colonic pH, which are the primary sites of lipid digestive enzymes. In accordance with certain aspects of the present disclosure, preferential release of MCT in the intestine and / or colon rather than the stomach may enhance the bioavailability of MCT, given the site of lipid digestive enzymes in these regions.

[0024]

[0046] In certain aspects of the present disclosure, the pharmaceutical composition provides preferential release of MCT with high drug loading in the lower gastrointestinal tract of the user.Without being limited by theory, preferential release of MCT in the lower gastrointestinal tract, including the colon, may reduce stomach upset and related adverse events compared to standard administration of non-formulated MCT oil.Furthermore, improved bioavailability of MCT may generally lead to increased ketone body production in vivo compared to standard administration of non-formulated MCT oil.

[0025]

[0047] In certain embodiments, the pharmaceutical composition may comprise a high drug loading of at least one MCT, such as caprylic triglyceride, 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, from about 30% by weight of the total composition to about 65% by weight of the total composition, from about 30% by weight of the total composition to about 60% by weight of the total composition, from about 40% by weight of the total composition to about 50% by weight of the total composition, from about 40% by weight of the total composition to about 45% by weight of the total composition, etc.

[0026]

[0048] As used herein, unless otherwise specified, "wt %" refers to "wt % of the total composition."

[0049] In certain aspects of the disclosure, MCT refers to any glycerol molecule esterified to three fatty acid molecules, each fatty acid molecule having a carbon chain of 5 to 12 carbons. In certain embodiments, the pharmaceutical composition comprises a glycerol molecule having the general formula:

[0027] [ka]

[0028] where R1, R2, and R3 are fatty acids having 5 to 12 carbons in their carbon backbone that are esterified to a glycerol backbone.

[0050] The MCTs of the present disclosure can be prepared by any process known in the art, such as direct esterification, rearrangement, fractionation, transesterification, etc. Sources of MCTs include any suitable source, semi-synthetic, synthetic, or natural. Examples of natural sources of MCTs include vegetable sources, such as coconut and coconut oil, palm kernel and palm kernel oil, and animal sources, such as milk from any of a variety of species (e.g., goat). For example, lipids can be prepared by rearrangement of vegetable oils, such as coconut oil. The length and distribution of chain lengths can vary depending on the source oil. For example, MCTs containing 1-10% C6, 30-60% C8, 30-60% C10, 1-10% C10 are typically obtained from palm oil and coconut oil.

[0029]

[0051] According to certain embodiments of the present disclosure, the pharmaceutical compositions of the present disclosure may include MCTs having greater than about 95% C8 at R1, R2, and R3, referred to herein as caprylic triglyceride ("CT"). Exemplary sources of CT include Miglyol® 808 or NEOBEE® 895. In certain aspects, CT can be obtained from coconut or palm kernel oil and is made by semi-synthetic esterification of octanoic acid to glycerin or the like.

[0030]

[0052] In other embodiments, the pharmaceutical composition may include MCTs in which R1, R2, and R3 are fatty acids containing a 6-carbon backbone (tri-C6:0). Tri-C6:0 MCTs are absorbed into the gastrointestinal tract very rapidly in some animal model systems. The high absorption rate results in rapid perfusion of the liver and a strong ketogenic response. In another embodiment, the pharmaceutical composition may include MCTs in which R1, R2, and R3 are fatty acids containing an 8-carbon backbone (tri-C8:0). In another embodiment, the pharmaceutical composition may include MCTs in which R1, R2, and R3 are fatty acids containing a 10-carbon backbone (tri-C10:0). In another embodiment, the pharmaceutical composition may include 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 include MCTs in which R1, R2, and R3 are a mixture of C6:0, C8:0, C10:0, and C12:0 fatty acids. In another embodiment, the pharmaceutical composition may comprise MCTs in which more than 95% of R1, R2 and R3 are 8 carbons in length. In yet another embodiment, the pharmaceutical composition may comprise MCTs in which R1, R2 and R3 carbon chains are 6 carbon chains or 10 carbon chains. In another embodiment, the pharmaceutical composition may comprise MCTs in which about 50% of R1, R2 and R3 are 8 carbons in length and about 50% of R1, R2 and R3 are 10 carbons in length. In one embodiment, the pharmaceutical composition may comprise MCTs in which R1, R2 and R3 are 6, 8, 10 or 12 carbon chains, or mixtures thereof.

[0031]

[0053] In certain aspects, the liquid pharmaceutical formulation of the present disclosure comprises one or more emulsion-forming excipients. In certain embodiments, the one or more emulsion-forming excipients may be any emulsifier that can form 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, citric acid esters of mono- and diglycerides (e.g., Citrem), monocaprylic acid propylene glycol (e.g., Capmul PG-8), and mono- and diglycerides of fatty acids, including combinations thereof. The emulsion-forming excipients may be present in an amount sufficient to produce the desired emulsion formation. For example, in certain embodiments, the emulsion-forming excipients may be present in an amount of about 1% to about 10% by weight of the total composition, about 1% to about 8% by weight of the total composition, about 1.3% to about 10% by weight of the total composition, etc.

[0032]

[0054] In some aspects, there are at least two emulsion-forming excipients in the composition, and at least one of the emulsion-forming excipients is present in an amount of at least 2.0% by weight of the total composition. In some aspects, the at least two emulsion-forming excipients are present in a 1:1 to 2:1 ratio relative to each other.

[0033]

[0055] In certain embodiments, the emulsion-forming excipients may include various combinations of lecithin, Kolliphor RH40, and caprylic acid ester emulsifiers, and optionally glycerol. In other embodiments, the emulsion-forming excipients may include various combinations of lecithin, sodium oleate, and optionally glycerol. In yet other embodiments, the emulsion-forming excipients may include Citrem alone or in combination with mono- and diglycerides of fatty acids.

[0034]

[0056] In certain embodiments, the liquid pharmaceutical formulation of the present disclosure may optionally include one or more flavoring or sweetening agents. In certain embodiments, the flavoring or sweetening agent may be present in an amount of 0.025% to 0.3% by weight, 0.15% to 0.3% by weight, 0.5% by weight for sweetening agents, 0.3% by weight for flavoring agents, etc., of the total composition. In certain embodiments, sucralose, stevia or similar sweetening agents may be used, with sucralose being preferred. In certain embodiments, vanilla, mango, berry or similar flavoring agents may be used, with vanilla being preferred. In some embodiments, the flavoring or sweetening agent may be oil-soluble.

[0035]

[0057] By way of non-limiting example, Table 1 below sets forth the attributes and properties of exemplary liquid pharmaceutical formulations.

[0036] [Table 1]

[0037]

[0058] By way of non-limiting example, suitable lecithins useful as emulsion-forming excipients in the present disclosure may be derived from any suitable source, such as eggs or soybeans. By way of non-limiting example, suitable lecithins may be selected from Soy PC, 95%, Avanti Number 441601; Egg PC, 95%, Avanti Number 131601, and the like.

[0038]

[0059] Any suitable mono- or diglyceride of fatty acids may be used as an emulsion former of the present disclosure, such as, for example, citric acid esters of mono- and diglycerides of fatty acids (Citrem) E472C; mono- and diglycerides of fatty acids E471; and the like.

[0039]

[0060] Any suitable method for making the pharmaceutical compositions of the present disclosure may be used. In certain aspects of the present disclosure, it has been found that reproducibility and emulsion stability can be controlled by modifying the manufacturing process as shown in the examples herein.

[0040]

[0061] In certain aspects, the present disclosure relates to a method of treating a disease or disorder associated with cognitive decline in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of the present disclosure in an amount effective to increase the ketone body concentration in said subject, thereby treating said disease or disorder. In certain embodiments, the pharmaceutical composition of the present disclosure may be administered outside the context of a ketogenic diet. For example, in the context of the present disclosure, carbohydrates may be consumed simultaneously with the pharmaceutical composition disclosed herein.

[0041]

[0062] According to certain aspects of the present disclosure, diseases and disorders involving cognitive decline include age-associated memory impairment (AAMI), Alzheimer's disease (AD), Parkinson's disease, Friedreich's ataxia (FRDA), GLUT1 deficiency epilepsy, leprechaunism, and Rabson-Mendenhall syndrome, coronary artery bypass graft (CABG) dementia, anesthesia-induced memory loss, Huntington's disease, migraine and related headaches, and many others.

[0042]

[0063] In another embodiment, the patient is at risk of or is at risk of developing cognitive decline associated with diseases resulting from decreased neuronal metabolism, such as cognitive decline associated with Alzheimer's disease (AD), Parkinson's disease, Friedreich's ataxia (FRDA), GLUT1 deficiency epilepsy, leprechaunism, and Rabson-Mendenhall syndrome, coronary artery bypass graft (CABG) dementia, anesthesia-induced memory loss, Huntington's disease, and many others.

[0043]

[0064] As used herein, neuronal metabolism reduction refers to all possible mechanisms that can lead to the reduction of neuronal metabolism. Such mechanisms include, but are not limited to, mitochondrial dysfunction, free radical attack, reactive oxygen species (ROS) generation, ROS-induced neuronal apoptosis, glucose transport or glycolysis failure, membrane ion potential imbalance, calcium flux dysfunction, etc.

[0044]

[0065] According to the present invention, high blood ketone levels will provide an energy source to brain cells with impaired glucose metabolism, leading to improved cognitive performance. As used herein, "subject" and "patient" are used interchangeably and refer to any mammal, including humans, that can benefit from treatment of diseases and conditions associated with or resulting from neuronal hypometabolism.

[0045]

[0066] "Effective amount" refers to the amount of the compound, material, or pharmaceutical composition described herein that is effective in achieving a particular biological result. The effectiveness of the treatment of the above-mentioned conditions can be evaluated by the improvement of the results from at least one neuropsychological test. These neuropsychological tests are known in the art and include, among others, the Clinical Global Impression of Change (CGIC), Rey Auditory Verbal Learning Test (RAVLT), First-Last Names Association Test (FLN), Telephone Dialing Test (TDT), Memory Assessment Clinics Self-Rating Scale (MAC-S), Symbol Digit Coding (SDC), SDC Delayed Recall Task (DRT), Divided Attention Test (DAT), Visual Sequence Comparison (VSC), DAT Dual Task (DAT Dual), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS).

[0046]

[0067] The term "cognitive function" refers to the specialized, normal, or proper physiological activity of the brain, including but not limited to at least one of the following: mental well-being, memory / recall ability, problem-solving ability, reasoning ability, thinking ability, judgment ability, learning ability, perception, intuition, attention, and consciousness. "Cognitive function enhancement" or "cognitive function improvement" refers to any improvement in the specialized, normal, or proper physiological activity of the brain, including but not limited to at least one of the following: mental well-being, memory / recall ability, problem-solving ability, reasoning ability, thinking ability, judgment ability, learning ability, perception, intuition, attention, and consciousness, measured by any means suitable in the art. "Cognitive function decline" or "cognitive dysfunction" refers to any decrease in the specialized, normal, or proper physiological activity of the brain.

[0047]

[0068] In another embodiment, the method of the present invention further comprises determining the genotype or specific allele of the patient.In one embodiment, the allele of the patient of the apolipoprotein E gene is determined.It was found that non-E4 carriers performed better than those with E4 alleles when the increase in ketone body level was induced by MCT.In addition, those with E4 alleles had higher fasting ketone body levels, and the levels continued to rise at 2-hour intervals.Therefore, E4 carriers may require higher ketone levels or drugs that enhance the ability to use existing ketone bodies.

[0048]

[0069] In one embodiment, the pharmaceutical composition of the present disclosure is administered orally.The therapeutically effective amount of therapeutic agent can be any amount or dose that is sufficient to produce desired effect, and depends in part on the severity and stage of condition, the size and condition of patient, and other factors that are easily known to those skilled in the art.Dosage can be given as a single dose, or as multiple doses that are divided over several weeks, for example, as discussed elsewhere herein.

[0049]

[0070] In one embodiment, the pharmaceutical compositions of the present disclosure are administered at a dosage required to increase blood ketone bodies to a level required to treat and / or prevent the occurrence of any disease-related or age-related cognitive decline, such as AD, AAMI, etc. Appropriate dosages can be determined by one skilled in the art.

[0050]

[0071] In one embodiment, oral administration of the pharmaceutical composition of the present disclosure results in hyperketonemia. Hyperketonemia, in one embodiment, results in ketone bodies that are utilized as energy in the brain even in the presence of glucose. Furthermore, hyperketonemia results in a significant (39%) increase in cerebral blood flow (Hasselbalch, SG, et al., Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia, Am J Physiol, 1996, 270:E746-51). Hyperketonemia has been reported to reduce cognitive dysfunction associated with systemic hypoglycemia in normal humans (Veneman, T., et al., Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans, Diabetes, 1994, 43:1311-7). It should be noted that systemic hypoglycemia is different from the local defects in glucose metabolism that occur in any disease-related or age-related cognitive decline, such as AD, AAMI, etc.

[0051]

[0072] Administration may be, for example, monthly, weekly, daily, or more than once a day, as needed or desired. Similarly, administration may be every other day, week, or month, every 2 days, week, or month, every 3 days, week, or month, etc. Administration may be multiple times a day. When utilized as a supplement to normal nutritional requirements, the composition may be administered directly to the patient, or may otherwise be contacted or mixed with daily feed or food.

[0052]

[0073] The pharmaceutical compositions provided herein are intended in one embodiment for "long term" consumption, sometimes referred to herein as "extended" periods. "Long term" administration, as used herein, generally refers to periods greater than one month. Periods greater than 2, 3, or 4 months comprise one embodiment of the invention. Also included are embodiments that include more extended periods, including periods greater than 5, 6, 7, 8, 9, or 10 months. Periods greater than 11 months or one year are also included. Longer term use spanning one, two, three, or more years is also contemplated herein. "Regular" as used herein refers to administration or consumption of the composition at least weekly. More frequent administration or consumption, such as two or three times per week, is included. Also included are regimens that include consumption at least once a day. Those skilled in the art will appreciate that the blood levels of ketone bodies or specific ketone bodies achieved can be a useful measure of administration frequency. Any frequency that allows the blood level of the compound being measured to be maintained within an acceptable range, whether or not explicitly exemplified herein, may be considered useful herein. Those skilled in the art will understand that the frequency of administration will be a function of the composition being consumed or administered, and that some compositions may require more or less frequent administration to maintain a desired blood level of the compound being measured (e.g., ketone bodies).

[0053]

[0074] Administration may be performed periodically, for example, as part of a treatment regimen in a patient. The treatment regimen may include having the patient take the pharmaceutical composition of the present disclosure periodically in an amount effective to enhance cognitive function, memory, and behavior in the patient. The 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 other day or week, every two days or weeks, every three days or weeks, every four days or weeks, or every five days or 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 the present disclosure exemplified herein.

[0054]

[0075] For example, a dosage of a composition of the invention, such as one comprising MCT, can be administered in an amount effective to enhance cognitive performance in patients suffering from diseases of neuronal metabolic decline, for example, in patients with any disease-related or age-related cognitive decline, such as AD, AAMI, etc.

[0055]

[0076] In one embodiment, the compositions of the present invention result in an increase in ketone levels in the body, in which the compositions are administered in an amount effective to induce hyperketonemia, in one embodiment, hyperketonemia results in ketone bodies being utilized for energy in the brain.

[0056]

[0077] In one embodiment, the composition increases the circulating concentration of at least one ketone body in a mammal or patient. In one embodiment, the circulating ketone body is D-beta-hydroxybutyrate. The amount of circulating ketone bodies can be measured at several time points after administration, in one embodiment, at a time point predicted to be close to the peak concentration in the blood, but can also be measured around the predicted peak blood concentration level. These off-peak measurements are then optionally adjusted to reflect the predicted level at the predicted peak. In one embodiment, the predicted peak time is about 2 hours. Peak circulating blood levels and timing can vary depending on factors known to those skilled in the art, including the individual's digestive rate, simultaneous or prior or post-ingestion of foods, beverages, etc., known to those skilled in the art. In one embodiment, the peak blood level achieved of D-beta-hydroxybutyrate is about 0.05 millimolar (mM) to about 50 mM. Another method of determining whether blood levels of D-beta-hydroxybutyrate are elevated to about 0.05 to about 50 mM is by measurement of D-beta-hydroxybutyrate urinary excretion in the range of about 5 mg / dL to about 160 mg / dL. In other embodiments, peak blood levels are elevated to about 0.1 to about 50 mM, about 0.1 to about 20 mM, about 0.1 to about 10 mM, about 0.1 to about 5 mM, and more preferably about 0.15 to about 2 mM, about 0.15 to about 0.3 mM, and about 0.2 to about 5 mM, although variations will necessarily occur depending, for example, on the formulation and the host, as discussed above. In other embodiments, the peak blood levels of D-beta-hydroxybutyrate achieved will be at least about 0.05 mM, at least about 0.1 mM, at least about 0.15 mM, at least about 0.2 mM, at least about 0.5 mM, at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 4 mM, at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, and at least about 50 mM.

[0057]

[0078] The effective amount of administration of the compound of the composition of the present invention, i.e., the compound capable of increasing ketone body levels in an amount effective for treating or preventing cognitive decline due to neuronal metabolism decline, will be apparent to one skilled in the art. As discussed herein above, such effective amount can be determined in light of the disclosed blood ketone levels. When the compound capable of increasing ketone body levels is MCT, the MCT dose in one embodiment will be in the range of about 0.05 g / kg / day to about 10 g / kg / day of MCT. In other embodiments, the dose will be in the range of about 0.25 g / kg / day to about 5 g / kg / day of MCT. In other embodiments, the dose will be in the range of about 0.5 g / kg / day to about 2 g / kg / day of MCT. In other embodiments, the dose will be in the range of about 0.1 g / kg / day to about 2 g / kg / day of MCT. In other embodiments, the dose of MCT is at least about 0.05 g / kg / day, at least about 0.1 g / kg / day, at least about 0.15 g / kg / day, at least about 0.2 g / kg / day, at least about 0.5 g / kg / day, at least about 1 g / kg / day, at least about 1.5 g / kg / day, at least about 2 g / kg / day, at least about 2.5 g / kg / day, at least about 3 g / kg / day, at least about 4 g / kg / day, at least about 5 g / kg / day, at least about 10 g / kg / day, at least about 15 g / kg / day, at least about 20 g / kg / day, at least about 30 g / kg / day, at least about 40 g / kg / day, and at least about 50 g / kg / day.

[0058]

[0079] As described herein, the composition is provided as a liquid formulation for administration to a subject in need of administration.The composition can be advantageously combined and / or used in combination with other therapeutic or preventive agents different from the disclosed MCT compounds.In many cases, administration in combination with the subject composition enhances the effectiveness of such agents.For example, the compound can be advantageously used in combination with antioxidants, compounds that enhance the efficiency of glucose utilization, and mixtures thereof.

[0059]

[0080] The daily dose of MCT can also be measured in grams of MCT per kg of body weight (BW) of the mammal. The daily dose of MCT can range from about 0.01 g / kg to about 10.0 g / kg BW of the mammal. Preferably, the daily dose of MCT is from about 0.1 g / kg to about 5 g / kg BW of the mammal. More preferably, the daily dose of MCT is from about 0.2 g / kg to about 3 g / kg BW of the mammal. Even more preferably, the daily dose of MCT is from about 0.5 g / kg to about 2 g / kg of the mammal. EXAMPLES

[0060]

[0081] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. General Materials and Methods

[0082] By way of example, exemplary liquid emulsions of the present disclosure can be made according to the procedure depicted in FIG. 1, mutatis mutandis, as needed and understood by one of skill in the art.

[0061]

[0083] By way of example, a particle size test method that may be used is as follows: procedure 1. Background measurement is performed using a pure water dispersion (milliQ-H2O) 2. Vortex the emulsion sample and add aliquots to the dispersion with a pipette until the obscuration is within the optimal range (5-15). The volume required is typically 10-100 μL depending on particle size, with smaller particle sizes requiring more volume. Wipe the outside of the pipette tip with a Kimwipe before addition to avoid any deposits forming on the outside of the tip due to evaporation. 3. Measurements are performed as three replicate submeasurements and results are reported as the average of the three submeasurements. 4. Agitation speed of dispersion unit = 3000 rpm Optical properties of materials (selected from the Matersizer software database) Lipid: Refractive index 1.6; Absorption: 0.1 Dispersion (milliQ-H2O): Refractive index 1.33; Absorption: 0.1 Equipment used: Mastersizer 2000 with Hydro 2000S dispersion unit; Malvern Measurement time Sample measurement time: 10 seconds Background measurement time: 10 seconds Sample measurement snap: 10000 Background measurement snap: 10000 Measurement Cycle Number of measurement cycles: 3 Delay between measurements: 10 seconds Average results were generated from three measurements Result calculation model General-purpose model Calculation Sensitivity: Normal (default)

[0084] By way of example, analytical test methods that may be used are as follows:

[0062] [Table 2]

[0063] [Table 3]

[0064] Example 1 - Phospholipon 90G, Kolliphor RH40, Capmul PG-8 Emulsion

[0085] In various embodiments, the liquid compositions of the present disclosure can be formulated using a combination of emulsion formers such as Phospholipon 90G (soybean lecithin), Kolliphor RH40 (PEG-40 hydrogenated castor oil), and Capmul PG-8 (propylene glycol monocaprylate).

[0065]

[0086] An exemplary process for making such a formulation is generally shown in FIG. 1 and summarized in the table below.

[0066] [Table 4]

[0067]

[0087] Exemplary emulsion former concentrations are shown in FIG. 2, and stability results are shown in the table below and in FIG.

[0068] [Table 5]

[0069]

[0088] It was found that the combinations and concentrations shown in the circled area in the lower right corner of Figure 3 were found to be the most stable formulations. An equal mix of Phospholipon 90G, Kolliphor RH40, and Capmul PG-8 was also extremely stable. The particle size evolution of Phospholipon 90G, Kolliphor RH40, and Capmul PG-8 emulsions prepared by Ultra Turrax emulsification is shown in Figure 4, and the particle size evolution of Phospholipon 90G, Kolliphor RH40, and Capmul PG-8 emulsions (prepared by Silverson and high pressure homogenizer emulsification) is shown in Figure 5. The appearance of Phospholipon 90G, Kolliphor RH40, and Capmul PG-8 emulsions under one month stability testing is shown in Figure 6.

[0070]

[0089] The chemical stability of an exemplary formulation is shown below.

[0071] [Table 6]

[0072]

[0090] Caprylic acid was not detected in the cases with 50% tricaprylin, 2% phospholipon 90G, 2% Kolliphor RH40, or 2% Capmul PG-8. Caprylic acid was not detected in any of the cases without Capmul PG-8.

[0073]

[0091] A summary of the findings is provided below.

[0074] [Table 7]

[0075]

[0092] Overall, both 50% tricaprylin, 4% Phospholipon 90G, 2% Kolliphor RH40 and 50% tricaprylin, 2% Phospholipon 90G, 2% Kolliphor RH40, 2% Capmul PG-8 have very good physical stability at one month. Caprylic acid was detected in the 50% tricaprylin, 2% Phospholipon 90G, 2% Kolliphor RH40, 2% Capmul PG-8 samples at one month. Reducing the total emulsifier concentration to 4% in 50% tricaprylin, 2.67% Phospholipon 90G, 1.33% Kolliphor RH40 only had a mild effect on the initial particle size.

[0076]

[0093] In another example, the effect of Kolliphor RH40 concentration was investigated. The Kolliphor content was reduced by increasing the lecithin-kolliphor ratio and / or decreasing the total emulsifier content. The results are shown below.

[0077] [Table 8]

[0078] Example 2 - Citrem and fatty acid mono- and diglyceride emulsions

[0094] In various embodiments, the liquid composition of the present disclosure can be formulated with a combination of emulsion-forming agents, such as Citrem and mono- and diglycerides of fatty acids.The emulsions prepared include: 20% tricaprylin, 0.8% Citrem, 0.5% monoglyceride in citrate buffer, pH 6 (two formulations are made using emulsifiers from different suppliers); 20% tricaprylin, 0.8% Citrem, 0.5% monoglyceride in milliQ-H20, pH 6; and 20% tricaprylin, 0.8% Citrem, 0.5% monoglyceride in milliQ-H20, pH 6.Exemplary particle size distributions are shown in Figure 7.

[0079]

[0095] Example 3 - Additional ingredient combinations

[0096] Additional research was conducted to improve stability and MCT concentration, and the results are shown below.

[0080] [Table 9]

[0081] [Table 10]

[0082]

[0097] 40% Tricaprylin, 3.2% 90G, 1.6% Citrem, 2.5% Glycerol;40% Tricaprylin, 2.13% 90G, 1.07% Citrem, 2.5% Glycerol;40% Tricaprylin, 2.13% 90G, 1.07% RH40;40% Tricaprylin, 2.13% 90G, 1.07% RH40, 2.5% Glycerol;40% Tricaprylin, 4.8% 90G, 2.5% Glycerol, 1% Sodium Oleate, 0.4% RH40, pH8;50% TC, 4% 90G, 2% RH40;40% Tricaprylin, 2.13% 90G, 1.07% RH40;40% Tricaprylin, 2.13% 90G, 1.07% Additional formulations were investigated including: RH40, 2.5% glycerol; 20% TC, 2.4% 90G, 2.5% glycerol, 0.5% sodium oleate, 0.2% RH40; 40% TC, 3.2% 90G, 1.6% Citrem, 2.5% glycerol; and 40% TC, 3.2% 90G, 1.6% RH40.

[0083]

[0098] Comparative Example 4: Lecithin, Sodium Oleate, Glycerol Emulsifier

[0099] In other embodiments, exemplary liquid formulations of the present disclosure can be prepared from combinations of emulsion formers (such as lecithin, sodium oleate and glycerol) ratios at different MCT concentrations. Formulations were prepared by Silverson vs. high pressure homogenization.

[0084] [Table 11]

[0085]

[0100] The emulsions were fairly stable but unlikely to meet the 12 month stability requirements at 25° C. Sodium oleate had a slight destabilizing effect at pH 7. Overall, these formulations were not pursued further based on the stability results.

[0086]

[0101] The stability results of the formulations prepared by Silverson mixer are shown in Figure 8 (stability results of 20% tricaprylin, 2.4% lecithin, different glycerols, different oleic acids), Figure 9 (visual stability results of 20% tricaprylin, 2.4% lecithin, different glycerols, different oleic acids), Figure 10 (stability results of 20% tricaprylin, 1.6% lecithin, different glycerols, different oleic acids), Figure 11 (stability results of 20% tricaprylin, 6.0% lecithin, different glycerols, different oleic acids), Figure 12 (visual stability results of 20% tricaprylin, 6.0% lecithin, different glycerols, different oleic acids), and Figure 13 (stability results of 20% tricaprylin, 4.0% lecithin, different glycerols, different oleic acids).

[0087]

[0102] The stability results of the formulations prepared by high pressure homogenization are shown in Figure 14 (stability results of 20% tricaprylin, 2.4% lecithin, different glycerols, different oleic acids), Figure 15 (visual stability results of 20% tricaprylin, 2.4% lecithin, different glycerols, different oleic acids), Figure 16 (stability results of 20% tricaprylin, 1.6% lecithin, different glycerols, different oleic acids), Figure 17 (stability results of 20% tricaprylin, 6.0% lecithin, different glycerols, different oleic acids), Figure 18 (visual stability results of 20% tricaprylin, 6.0% lecithin, different glycerols, different oleic acids), and Figure 19 (stability results of 20% tricaprylin, 4.0% lecithin, different glycerols, different oleic acids).

[0088]

[0103] Example 5 - Bioburden Reduction Method

[0104] Methods for bioburden reduction of formulations of the present disclosure are provided below.

[0089] [Table 12]

[0090]

[0105] As part of the development process, a series of bioburden reduction strategies were evaluated for their effectiveness and feasibility for incorporation into the manufacturing process. Details of the various tests performed are summarized below.

[0091]

[0106] filtration

[0107] Incorporation of filtration as a bioburden reduction step can be used as the simplest method to reduce microbial burden (if present). Filter compatibility studies were performed by Pall Filtration to evaluate the microbial retention of selected filters. These studies confirmed that the selected formulations were sensitive to the type of filter media and that the preferred media type did not retain microorganisms.

[0092]

[0108] dry heat

[0109] Heating is a commonly accepted method of reducing bioburden. Evaluation of heating conditions commonly used to control microbial growth was attempted on the exemplary formulation. All temperature conditions tested showed significant disruption to the PSD profile of the product, confirming that heating is not a viable method of bioburden control. This observation correlates with the degradation of the product with elevated temperatures observed in developmental testing.

[0093]

[0110] Gamma irradiation

[0111] Gamma irradiation is a commonly accepted method for sterilizing components and reducing bioburden in natural materials. Exemplary formulations were irradiated at various doses and then the impact of irradiation on product performance was evaluated. The study confirmed that a 10kG dose was effective in achieving a 6 log reduction in bioburden and had no impact on the critical quality attributes of the products tested.

[0094]

[0112] The following table shows the effect of various doses of gamma irradiation on tricaprylin and a representative formulation ("Formulation 2" 50% tricaprylin, 2.67% Phospholipon 90G, 1.33% Kolliphor RH 40, 50 mM phosphate buffer pH 6.8).

[0095] [Table 13-1]

[0096] [Table 13-2]

[0097] [Table 13-3]

[0098]

[0113] No microorganisms were detected in Formulation 2 before or after gamma irradiation. Results from biological indicator strips confirmed that gamma irradiation was successful, as a 6-log reduction in bioburden was achieved at all doses tested.

[0099]

[0114] Physiochemical evaluation of formulation samples irradiated at 10 kGy confirmed no changes in appearance, assay, related substance profile, particle size distribution or pH. Irradiated samples also demonstrated no negative effects from gamma irradiation on the primary container and closure for all doses evaluated; i.e., no embrittlement of seals was observed as a result of irradiation.

[0100]

[0115] Samples irradiated at 15 and 25 kGy also showed no changes to appearance, assay and pH, although the related substance profile and particle size distribution were affected at these doses. In this regard, the particle size distribution of the gamma irradiated samples appears to be more affected than the retained samples. The results are shown in Figure 20.

[0101]

[0116] Example 6 - Exemplary and Comparative Formulations

[0117] The following formulations of the present disclosure and comparative formulations were prepared according to the general methodology of FIG. 1, which may be modified as needed and as understood by one of skill in the art.

[0102] [Table 14-1]

[0103] [Table 14-2]

[0104] [Table 15]

[0105] [Table 16]

[0106] [Table 17]

[0107]

[0118] Example 7 - Long-term stability

[0119] The following formulations of the present disclosure and comparative formulations were prepared according to the general methodology of Figure 1, which may be modified as needed and as understood by one of skill in the art. Exemplary long-term stability results are shown in the table below.

[0108] [Table 18]

[0109] [Table 19]

[0110] [Table 20-1]

[0111] [Table 20-2]

[0112] [Table 21]

[0113] [Table 22]

[0114] [Table 23]

[0115] [Table 24]

[0116] [Table 25]

[0117] [Table 26]

[0118]

[0120] Example 8 - Flavoring Agents

[0121] Additional research was conducted to improve the taste and overall palatability of the liquid pharmaceutical formulations of the present disclosure. Various sweeteners and flavoring agents were investigated. The results are presented below.

[0119]

[0122] Sweetener

[0123] Three levels of sucralose (0.025%, 0.05%, and 0.1%) and three levels of stevia (0.1%, 0.2%, and 0.3%) were compared. No obvious sweetener differences were identified between sucralose and stevia, as the flavoring agent prevailed. However, sucralose was slightly preferred because it could be used at lower concentrations (i.e., 0.05% to 0.1% sucralose was found to provide a sufficient level of sweetness).

[0120]

[0124] Flavoring Agent

[0125] Various flavoring agents were compared (at a concentration of 0.1% sucralose). Concentrations were selected based on manufacturer recommendations and initial testing.

[0121] [Table 27]

[0122]

[0126] Oil soluble flavoring agents have unexpectedly been found to provide improved taste and overall palatability to the liquid pharmaceutical formulations of the present disclosure.

[0127] Example 9 - Lead formulation selection

[0128] Based on the above formulations and comparative formulation preparations, the following lead formulations were selected:

[0123] [Table 28]

[0124]

[0129] Rationale for lead formulation selection: · Primary physical and chemical stability The range of tricaprylin concentrations and the presence or absence of glycerol, as well as the combination of excipients selected, as these factors may affect the PK profile All lead formulations exhibit relatively fast digestion profiles. · Citrem formulations are physically and chemically stable but may pose some manufacturing related issues (particle size may be affected by filtration, GC analysis). · Sodium oleate formulations have been shown to be temperature sensitive and may pose some manufacturing and storage related limitations. Nevertheless, they remain the lead candidates selected as they represent different excipient combinations that may offer interesting variations from a PK and tolerability perspective.

[0125]

[0130] 21A-21J show particle size distributions at various time points for the indicated lead formulations AC-OLE-1 through AC-OLE-10.

[0131] Example 11 - pK Study of Lead Formulations

[0132] The lead formulations of Example 10 (AC-OLE-1 through AC-OLE-10) were administered to healthy volunteers to investigate the pharmacokinetic effects of the liquid formulations of the present disclosure.

[0126]

[0133] The study will include several study sites and cycles. At the Eastern site and each cycle, several of the lead formulations (up to four) will be tested in up to 20 healthy volunteers in a partial or complete crossover design. Upon completion of each cycle, blood parameters will be analyzed.

[0127]

[0134] As shown in FIG. 22A (Cmax for total ketones (BHB+AcA)) and FIG. 22B (AUC for total ketones (BHB+AcA)) calculated as the area under the curve (AUC) for total ketones (BHB+AcA), all lead formulations demonstrated a total ketone Cmax above 700 μM, with most above 1000 μM (and generally comparable to the lead formulation AC-1202).

[0128]

[0135] All publications and patent applications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0129]

[0136] Although the present invention has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for the elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings without departing from the essential scope thereof. Therefore, it is not intended that the invention be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but the invention is intended to include all embodiments falling within the scope of the appended claims.

Claims

**Claim 1** A liquid pharmaceutical composition comprising at least about 30% by weight of tricaprylin in the whole composition and one or more emulsion-forming excipients present in a concentration sufficient to form an emulsion stable for at least one month under ambient conditions. **Claim 2** The liquid pharmaceutical composition according to claim 1, wherein the one or more emulsion-forming excipients are selected from the group consisting of lecithin, hydrogenated castor oil, caprylic acid esters, sodium oleate, glycerol, citric acid esters of monoglycerides and diglycerides of fatty acids, monoglycerides and diglycerides of fatty acids including monopropylene glycol monocaprylate, and combinations thereof. **Claim 3** The liquid pharmaceutical composition according to claim 1, wherein the one or more emulsion-forming excipients are selected from the group consisting of lecithin, hydrogenated castor oil, caprylic acid ester emulsifiers, glycerol, and combinations thereof. **Claim 4** The liquid pharmaceutical composition according to claim 1, wherein the one or more emulsion-forming excipients are selected from the group consisting of lecithin, sodium oleate, glycerol, and combinations thereof. **Claim 5** The liquid pharmaceutical composition according to claim 1, wherein the one or more emulsion-forming excipients are selected from the group consisting of Citrem, monoglycerides and diglycerides of fatty acids, and combinations thereof. **Claim 6** The liquid pharmaceutical composition according to any one of claims 1-5, wherein the tricaprylin is present in an amount of about 30% to about 60% by weight of the whole composition. **Claim 7** The liquid pharmaceutical composition according to any one of claims 1-5, wherein the one or more emulsion-forming excipients are present in an amount of about 1% to about 10% by weight of the whole composition. **Claim 8** The liquid pharmaceutical composition according to any one of claims 1-5, wherein at least two emulsion-forming excipients are present in the composition, and at least one of the emulsion-forming excipients is present in an amount of at least 2.0% by weight of the whole composition. **Claim 9** The liquid pharmaceutical composition according to claim 8, wherein the at least two emulsion-forming excipients are present in a ratio of 1:1 to 2:1 with respect to each other. **Claim 10** The liquid pharmaceutical composition according to any one of claims 1 - 5, wherein the stable emulsion exhibits an average particle size of less than 0.5 μm for at least one month under ambient conditions.

11. The liquid pharmaceutical composition according to any one of claims 1 - 5, further comprising an oil-soluble flavoring agent.

12. The liquid pharmaceutical composition according to any one of claims 1 - 5, for use in a method of treating a disease or disorder associated with cognitive decline in a subject in need of treatment for a disease or disorder associated with cognitive decline, the method comprising administering the liquid pharmaceutical composition to the subject in an amount effective to increase the ketone body concentration in the subject, thereby treating the disease or disorder.

13. The liquid pharmaceutical composition according to claim 12, wherein the disease or disorder associated with cognitive decline is selected from Alzheimer's disease and age-related memory impairment.

14. The liquid pharmaceutical composition according to claim 12, wherein the method further comprises determining whether the subject lacks the ApoE4 genotype.

15. The liquid pharmaceutical composition according to claim 12, wherein the composition is administered at a dose of about 0.05 g / kg / day to about 10 g / kg / day.

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