Formulations of lipid nanoemulsions with controlled pharmacokinetic properties and methods of making and using the same

Abstract

Provided herein are emulsion compositions comprising tricaprylin. In addition, additional ingredients are described herein to make these emulsion compositions more suitable for oral ingestion. Methods of making and using these emulsions are described herein. The described emulsions can be used for oral administration of tricaprylin to treat and / or prevent various diseases or disorders.

Description

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 608,271, filed December 10, 2023, and U.S. Provisional Patent Application Serial No. 63 / 602,622, filed November 26, 2023, each of which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure generally relates to compositions and methods of preparing oral liquid emulsions of medium-chain triglycerides (MCTs). Background Technology

[0003] Tricaprylyl glycerol (synonymously known as tricaprylin, trioctanoylglycerol, tricaprylyl glycerol, tricapryloyl glycerol, tricaprylyl glycerol, octanoic acid-1,2,3-propanetriyl-ester, tricapryl glycerol ester, tricaprylyl glycerol ester, tricapry ...

[0004] Tricaprylic acid glycerides are used in pharmaceutical formulations, for example, as a neutral carrier or excipient, as an absorption enhancer, and as a solubilizer for active pharmaceutical ingredients. It is also used as an oil phase in the preparation of water-in-oil-in-water multiple emulsions, for introducing water-soluble drugs, and for obtaining stable microcapsules. Due to its miscibility with natural oils and surfactants, tricaprylic acid glycerides are used as the fatty component in two-phase foam baths. Furthermore, due to its compatibility with organic and inorganic filter agents, it is used in sunscreens and oils. It is also used as a fixative in perfumes and fragrances. However, as noted above, fatty acid polyol esters, particularly fatty acid glycerides, and especially so-called medium-chain triglycerides (MCTs) and especially tricaprylic acid glycerides, have also been used as active ingredients or active compounds in pharmaceutical compositions. Summary of the Invention

[0005] In some aspects, this disclosure covers emulsions comprising: about 20-60 wt% glyceryl tricaprylate; about 0.1-10 wt% emulsifier; about 0.1-10 wt% glycerol; and about 10 mM-200 mM phosphate buffer (pH 6.0-7.5). Non-limiting examples of emulsifiers include phospholipids, polyethylene glycol glycerol hydroxystearate, citrates of monoglycerides and diglycerides, or any combination thereof. In some aspects, the emulsifier is Phospholipon® 90G, Kolliphor® RH40, or a combination thereof. In some aspects, emulsions are provided herein comprising: 50 wt% glyceryl tricaprylate; 4 wt% Phospholipon® 90G; 2 wt% Kolliphor RH40; 2.5 wt% glycerol; and 20 mM-150 mM phosphate buffer (pH 6.8). In some aspects, the emulsion may additionally contain a sweetener. Non-limiting examples of suitable sweeteners include acesulfame potassium, advantian, aspartame, saccharin, sucralose, monk fruit, stevia, or any combination thereof. In some aspects, the sweetener is sucralose, stevia, or any combination thereof. In some aspects, the emulsion contains about 0.01% to about 1% by weight of a sweetener. In an exemplary aspect, the sweetener is sucralose and is present at a concentration of about 0.05% by weight. In some aspects, the emulsion additionally contains a flavoring agent (flavoring agent). In some aspects, the flavoring agent is oil-soluble. Non-limiting examples of flavoring agents include vanilla, berries, and mango. In some aspects, the flavoring agent is vanilla. In some aspects, the emulsion contains about 0.1% to about 0.3% by weight of vanilla flavoring agent. In some aspects, the vanilla flavoring agent is present at a concentration of about 0.1% by weight or about 0.2% by weight. In some formulations, the emulsion contains 100 mM phosphate buffer and 0.1% by weight vanilla flavoring. In other formulations, the emulsion contains 50 mM phosphate buffer and vanilla flavoring at a concentration of approximately 0.2% by weight.

[0006] In some aspects, an emulsion is disclosed herein comprising: a medium-chain triglyceride (MCT); one or more emulsifiers; a buffer; and a sweetener and / or flavoring agent; wherein the emulsion is for oral administration. In some aspects, the MCT is glyceryl tricaprylate. Non-limiting examples of emulsifiers include phospholipids, polyethylene glycol glyceryl hydroxystearate, citrates of monoglycerides and diglycerides, or combinations thereof. In some aspects, the emulsion further comprises a triol. In some aspects, the triol comprises glycerol. Non-limiting examples of sweeteners include acesulfame potassium, advansane, aspartame, saccharin, sucralose, monk fruit, purified stevia leaf extract, or combinations thereof. In some aspects, the sweetener is sucralose, stevia, or any combination thereof. In some aspects, the emulsion comprises about 0.01% by weight to about 1% by weight of a sweetener. In an exemplary aspect, the sweetener is sucralose and is present at a concentration of about 0.05% by weight. In some aspects, the emulsion contains an oil-based flavoring agent. In some aspects, the flavoring agent includes vanilla, mango, berries, or combinations thereof. In some aspects, the flavoring agent is present in an amount from about 0.05% by weight to about 0.5% by weight. In some aspects, the flavoring agent includes vanilla. In some aspects, vanilla is present at a concentration of about 0.1% by weight or about 0.2% by weight. In some aspects, the flavoring agent includes berries. In some aspects, the flavoring agent is present at a concentration of about 0.3% by weight.

[0007] In some respects, the emulsions disclosed herein are stable at about 2°C to about 8°C for a period of at least about 3 months, 6 months, 9 months, 12 months, or longer. In some respects, the emulsions are stable at about 25°C for a period of 3 months, 6 months, 9 months, 12 months, or longer. In some respects, the emulsions are stable at about 40°C for a period of 3 months, 6 months, 9 months, 12 months, or longer.

[0008] In some aspects, this document also discloses a method for preparing an emulsion containing glyceryl tricaprylate, wherein the method comprises the following steps: a) feeding a component comprising a buffer, glyceryl tricaprylate, and one or more emulsifiers into a container; b) mixing the buffer, glyceryl tricaprylate, and one or more emulsifiers in the container under high shear to form a crude emulsion; c) optionally sterilizing the crude emulsion to form a sterile emulsion; and d) homogenizing the sterile emulsion under high pressure (HPH) to form an emulsion containing glyceryl tricaprylate. In some aspects, step a may also include feeding glycerol into the container. In some aspects, step (c) comprises an ultrathermal heat treatment (UHT) step, an irradiation step, or a combination thereof. In some aspects, step (c) comprises a UHT step. In some aspects, the UHT step (step c) is performed at a temperature of about 130°C to about 145°C for about 3 seconds to about 45 seconds. In some aspects, the temperature is about 135°C and the holding time is about 2-3 seconds. In some aspects, step (c) does not include an irradiation step. In some aspects, the method further includes mixing the flavoring agent with tricaprylic acid glyceride in step (a). In some aspects, the method further includes mixing the sweetener with tricaprylic acid glyceride in step (a). In some aspects, one or more emulsifiers include Phospholipon® 90G, Kolliphor® RH40, or combinations thereof. In some aspects, the method does not include a gamma irradiation step for sterilization. In some aspects, the emulsion is an emulsion as disclosed above. In some aspects, the emulsion prepared by the disclosed method is stable for at least 3 months, at least 6 months, or at least 12 months. In some aspects, the emulsion has a particle size of 0.01-10 µm. In some aspects of the disclosed method, high-pressure homogenization is performed at a pressure of about 5,000 PSI to about 10,000 PSI. In some aspects, high-pressure homogenization is performed at a pressure of about 7,500 PSI. In some aspects, the method further includes a high-shear mixing step with recirculation.

[0009] In some aspects, this document also discloses methods for treating a disease or disorder in a subject in need, the method comprising administering to the subject an effective amount of the disclosed emulsion. In some aspects, this document also discloses methods for treating a disease or disorder in a subject in need, the method comprising administering to the subject an effective amount of an emulsion comprising: about 20%-60% by weight of caprylic / caprylic acid glyceride; about 0.1-10% by weight of an emulsifier; about 0.1-10% by weight of glycerol; and about 10 mM-200 mM phosphate buffer (pH 6.0-7.5). In some aspects, the emulsion comprises: 50% by weight of caprylic / caprylic acid glyceride; 4% by weight of Phospholipon® 90G; 2% by weight of Kolliphor® RH40; 2.5% by weight of glycerol; and 20 mM-100 mM phosphate buffer (pH 6.8). Non-limiting examples of diseases or disorders that can be treated with the disclosed emulsion include age-related memory disorder (AAMI), Alzheimer's disease (AD), Parkinson's disease, Friedreich's ataxia (FRDA), GLUT1 deficiency epilepsy, dwarfism syndrome, Rabson-Mendenhall syndrome, coronary artery bypass graft (CABG) dementia, anesthesia-induced memory loss, Huntington's disease, infantile spasms, migraine, and related headaches. Attached Figure Description

[0010] The following figures form part of this specification and are included to further illustrate certain aspects of this disclosure. A better understanding of these aspects can be achieved by referring to one or more of these figures in conjunction with the detailed description of the specific aspects presented herein:

[0011] Figure 1 A method for manufacturing an unflavored emulsion for preparing AC-OLE-01 is shown.

[0012] Figure 2 A manufacturing method with potential flavoring addition points marked by red asterisks is shown. At the beginning of the method, sucralose is mixed with a buffer and emulsifier (1), or added with vanilla flavoring, followed immediately by filling (2), as highlighted in gray text.

[0013] Figure 3 The manufacturing method is shown with flavoring addition points marked by gray asterisks. At the beginning of the method, sucralose is mixed with buffer and emulsifier, as highlighted in gray text.

[0014] Figure 4The particle size distribution of AC-OLE-01-VA (an active formulation flavored with 0.2% Intense Vanilla Flavor and 0.05% sucralose) is shown after high-shear mixing (top) and after seven passes of high-pressure homogenization (bottom).

[0015] Figures 5A-5I show the pH evolution of the DOE formulations screened at 25°C, ranked from most stable to least stable, as shown for each batch in each figure.

[0016] Figures 6A-6D The pH evolution of the active formulation with different levels of flavoring agent and buffer concentration is shown in the figures above. Figure 6A The pH of the active formulation containing 50 mM buffer and 0.2% vanilla is provided. Figure 6B The pH of the active formulation containing 100 mM buffer and 0.2% vanilla is provided. Figure 6C The pH of the active formulation containing 100 mM buffer and 0.1% vanilla is provided. Figure 6D The pH of the unflavored active formulation with 100 mM buffer is provided.

[0017] Figure 7 A manufacturing method including UHT treatment is shown.

[0018] Figures 8A-8B This shows that after high shear mixing ( Figure 8A ) and after 5 passes of high-pressure homogenization ( Figure 8B Particle size measurement during the process.

[0019] Figure 9 A method for preparing a vanilla-flavored emulsion is shown.

[0020] Figures 10A-10B This illustrates the effect of one of the active formulations after high-shear mixing. Figure 10A ) and after the second high-pressure homogenization ( Figure 10B Particle size measurement during the process.

[0021] Figure 11 An alternative manufacturing method is shown, which uses a mixture of dihydrogen phosphate and disodium hydrogen phosphate as a buffer, features high-shear mixing with recirculation, and uses 7,500 PSI instead of 10,000 PSI for high-pressure homogenization. Detailed Implementation

[0022] The following detailed description is made with reference to the accompanying drawings, which illustrate various aspects of this disclosure. The drawings and description are intended to describe aspects of this disclosure in sufficient detail to enable those skilled in the art to practice it. Other components may be utilized and changes may be made without departing from the scope of this disclosure. Therefore, the following description is not limiting.

[0023] I. Emulsion Formulations

[0024] This disclosure relates to emulsions that contain a pharmaceutically active ingredient, one or more emulsifiers, and a buffer solution. In some aspects, the emulsion may include alcohols, sweeteners, flavoring agents, or combinations thereof.

[0025] In some cases, the active pharmaceutical ingredient can be an oil. In other cases, the active pharmaceutical ingredient is a medium-chain triglyceride (MCT).

[0026] In some respects, the pharmaceutical ingredient is caprylic / caprylic acid glyceride. The amount of the active pharmaceutical ingredient in the emulsion can range from about 10 wt% to about 60 wt%. For example, the active pharmaceutical ingredient can be about 10 wt% to about 15 wt%, about 15 wt% to about 20 wt%, about 20 wt% to about 25 wt%, about 25 wt% to about 30 wt%, about 30 wt% to about 35 wt%, about 35 wt% to about 40 wt%, about 40 wt% to about 45 wt%, about 45 wt% to about 50 wt%, about 50 wt% to about 55 wt%, or about 55 wt% to about 60 wt%.

[0027] In some respects, the emulsion comprises or is substantially composed of: tricaprylic acid glycerides, one or more emulsifiers, buffers, sweeteners and / or flavoring agents, and optional alcohols.

[0028] In some respects, buffers contain physiologically safe buffers. In some respects, buffers maintain pH stability without interfering with cell function and enzyme activity. In some respects, buffers may contain, or consist essentially of, the following: phosphate buffer (a mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate in an amount sufficient to achieve the desired pH, or pH adjusted with sodium hydroxide), citrate buffer, acetate buffer, MOPS buffer (3-(N-morpholino)propanesulfonic acid), PIPES (piperazine-N,N′-bis(2-ethanesulfonic acid)), MES (2-(N-morpholino)ethanesulfonic acid), or any combination thereof.

[0029] The buffer solution can have a concentration of about 50 mM to about 200 mM, or about 50 mM to about 150 mM. For example, the concentration can be in the range of about 50 mM to about 60 mM, about 60 mM to about 70 mM, about 70 mM to about 80 mM, about 80 mM to about 90 mM, about 90 mM to about 100 mM, or about 110 nM to about 110 mM, or about 110 nM to about 120 mM, or about 120 nM to about 130 mM, or about 130 nM to about 140 mM, or about 140 nM to about 150 mM. The pH of the buffer solution can be in the range of about 6.5 to about 8.0. For example, the pH can be in the range of about 6.5 to about 6.6, about 6.6 to about 6.7, about 6.7 to about 6.8, about 6.8 to about 6.9, about 6.9 to about 7.0, about 7.0 to about 7.1, about 7.1 to about 7.2, about 7.2 to about 7.3, about 7.3 to about 7.4, about 7.4 to about 7.5, about 7.6 to about 7.7, about 7.7 to about 7.8, about 7.8 to about 7.9, or about 7.9 to about 8.0. In some aspects, the buffer is a phosphate buffer. In some aspects, the phosphate buffer has a concentration of about 50 mM to about 200 mM, or about 50 mM to about 110 mM. For example, the concentration can be in the range of about 50 mM to about 60 mM, about 60 mM to about 70 mM, about 70 mM to about 80 mM, about 80 mM to about 90 mM, about 90 mM to about 100 mM, or about 110 nM to about 110 mM. The pH of the phosphate buffer can be in the range of about 6.5 to about 8.0. For example, the pH can be in the following ranges: about 6.5 to about 6.6, about 6.6 to about 6.7, about 6.7 to about 6.8, about 6.8 to about 6.9, about 6.9 to about 7.0, about 7.0 to about 7.1, about 7.1 to about 7.2, about 7.2 to about 7.3, about 7.3 to about 7.4, about 7.4 to about 7.5, about 7.6 to about 7.7, about 7.7 to about 7.8, about 7.8 to about 7.9, or about 7.9 to about 8.0.

[0030] In some aspects, one or more emulsifiers include phospholipids, polyethylene glycol glycerol hydroxystearate, citrates of monoglycerides and diglycerides, sodium salts of oleic acid, or combinations thereof. In some aspects, one or more emulsifiers may include Phospholipon® 90G, Kolliphor® RH40, citrem, sodium oleate, or combinations thereof. In some aspects, the emulsifier includes Phospholipon® 90G.

[0031] Phospholipon® 90G is a highly purified phospholipid derived from soybean lecithin, primarily composed of phosphatidylcholine with a content of at least 94%. It is available in granulated form and is commonly used in various pharmaceutical and cosmetic applications due to its emulsifying, solubilizing, and stabilizing properties. Phospholipon® 90G is identified by CAS number 97281-47-5. Alternative chemical names include (soy)phosphatidylcholine, (soy) lecithin, lecithinone, phospholutein, and PtdCho.

[0032] In some applications, the emulsifier includes Kolliphor® RH40. Kolliphor® RH40 is a nonionic solubilizer and emulsifier manufactured by BASF. It is derived from the reaction of hydrogenated castor oil with ethylene oxide, specifically a combination of 1 mole of hydrogenated castor oil and 40 moles of ethylene oxide. Alternative chemical names include: Polyoxyethylene 40 Hydrogenated Castor Oil (USP), Polyethylene Glyceryl Hydroxystearate, and has CAS number: 61788-85-0. It forms a white to slightly yellow paste at 20°C, with an HLB value between 14 and 16, and is generally odorless and tasteless in aqueous solution.

[0033] In some applications, emulsifiers include citrem. Citrem (an abbreviation for citrate esters of monoglycerides and diglycerides) is an emulsifier commonly used in the food and pharmaceutical industries. It is derived from the esterification of citric acid with monoglycerides and diglycerides of fatty acids, typically derived from vegetable oils. Due to the diversity of possible formulations and ester compositions, the CAS number for citrem comes from various entries.

[0034] In some respects, the sweetener may be acesulfame potassium, advantran, aspartame, saccharin, sucralose, monk fruit, purified stevia leaf extract, or a combination thereof. In other respects, the sweetener may be sucralose, stevia, or any combination thereof.

[0035] In some respects, the alcohol can be a triol. Suitable triols include, but are not limited to, glycerol, 1,2,3-butanetriol, trimethylolpropane erythritol, and triethanolamine. In some respects, the triol is glycerol.

[0036] The flavoring agent may be oil-based. In some cases, the flavoring agent may include vanilla, mango, or berries. In some cases, the flavoring agent may be vanilla. In some cases, the flavoring agent may be a strong vanilla flavoring (Sensient®). In some cases, the flavoring agent may be berries. In some cases, the flavoring agent may be Sensient® Berry.

[0037] The total amount of one or more emulsifiers in the emulsion can be from about 0.1 wt% to about 10 wt% or from about 2 wt% to about 8 wt%. For example, one or more emulsifiers can be from about 2 wt% to about 2.5 wt%, from about 2.5 wt% to about 3.0 wt%, from about 3.0 wt% to about 3.5 wt%, from about 4.0 wt% to about 4.5 wt%, from about 4.5 wt% to about 5.0 wt%, from about 5.0 wt% to about 5.5 wt%, from about 5.5 wt% to about 6.0 wt%, from about 6.5 wt% to about 7.0 wt%, from about 7.0 wt% to about 7.5 wt%, or from about 7.5 wt% to about 8.0 wt%.

[0038] The amount of phosphate buffer in the emulsion can range from about 40 wt% to about 80 wt%. For example, the phosphate buffer can be about 40 wt% to about 45 wt%, about 45 wt% to about 50 wt%, about 50 wt% to about 55 wt%, about 55 wt% to about 60 wt%, about 60 wt% to about 65 wt%, about 65 wt% to about 70 wt%, about 70 wt% to about 75 wt%, or about 75 wt% to about 80 wt%.

[0039] In some respects, the flavoring agent may be present in amounts from about 0.1 wt% to about 0.4 wt%. For example, the flavoring agent may be present in amounts of about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, and about 0.4 wt%.

[0040] In some respects, vanilla may be present in amounts from about 0.01 wt% to about 0.2 wt%. For example, vanilla may be present in amounts of about 0.1 wt%, about 0.11 wt%, about 0.12 wt%, about 0.13 wt%, about 0.14 wt%, about 0.15 wt%, about 0.16 wt%, about 0.17 wt%, about 0.18 wt%, about 0.19 wt%, or about 0.2 wt%.

[0041] In some respects, the sweetener may be present in an amount of about 0.01 wt% to about 0.1 wt%. For example, the sweetener may be present in an amount of about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, or about 0.1 wt%.

[0042] In some respects, the emulsion can be stable at approximately 2°C to approximately 8°C, approximately 25°C, or approximately 40°C for a period of 3 months.

[0043] In some aspects, the emulsion comprises about 50 wt% caprylic / caprylic acid ester, about 4 wt% Phospholipon® 90G, about 2 wt% Kolliphor® RH40, about 2.5 wt% glycerol, and about 50 mM phosphate buffer. In other aspects, the emulsion comprises about 50 wt% caprylic / caprylic acid ester, 4 wt% Phospholipon® 90G, about 2 wt% Kolliphor® RH40, about 2.5 wt% glycerol, about 50 mM phosphate buffer, and about 0.01 wt% to about 0.1 wt% sweetener. For example, the amount of sweetener may be about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, or about 0.1 wt%. The sweetener may be sucralose, stevia, or any combination thereof. In some aspects, the emulsion includes about 50 wt% caprylic / caprylic acid glyceride, about 4 wt% Phospholipon® 90G, about 2 wt% kolliphor RH40, about 2.5 wt% glycerol, about 50 mM phosphate buffer, about 0.01 wt% to about 0.1 wt% of the sweetener, and about 0.1 wt% to about 0.3 wt% of the flavoring agent. For example, the flavoring agent may be approximately 0.1 wt%, approximately 0.11 wt%, approximately 0.12 wt%, approximately 0.13 wt%, approximately 0.14 wt%, approximately 0.15 wt%, approximately 0.16 wt%, approximately 0.17 wt%, approximately 0.18 wt%, approximately 0.19 wt%, approximately 0.20 wt%, approximately 0.21 wt%, approximately 0.22 wt%, approximately 0.23 wt%, approximately 0.24 wt%, approximately 0.25 wt%, approximately 0.26 wt%, approximately 0.27 wt%, approximately 0.28 wt%, approximately 0.29 wt%, or approximately 0.30 wt%. The flavoring agent may be oil-soluble.

[0044] In some aspects, the emulsion comprises about 50 wt% caprylic / caprylic acid ester, about 4 wt% Phospholipon® 90G, about 2 wt% Kolliphor® RH40, about 2.5 wt% glycerol, and about 100 mM phosphate buffer. In other aspects, the emulsion comprises about 50 wt% caprylic / caprylic acid ester, about 4 wt% Phospholipon® 90G, about 2 wt% Kolliphor® RH40, about 2.5 wt% glycerol, about 100 mM phosphate buffer, and about 0.01 wt% to about 0.1 wt% sweetener. For example, the amount of sweetener may be about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, or about 0.1 wt%. The sweetener may be sucralose, stevia, or any combination thereof. In some aspects, the emulsion includes about 50 wt% caprylic / caprylic acid glyceride, about 4 wt% Phospholipon® 90G, about 2 wt% Kolliphor® RH40, about 2.5 wt% glycerol, about 100 mM phosphate buffer, about 0.01 wt% to about 0.1 wt% of the sweetener, and about 0.1 wt% to about 0.3 wt% of the flavoring agent. For example, the flavoring agent may be approximately 0.1 wt%, approximately 0.11 wt%, approximately 0.12 wt%, approximately 0.13 wt%, approximately 0.14 wt%, approximately 0.15 wt%, approximately 0.16 wt%, approximately 0.17 wt%, approximately 0.18 wt%, approximately 0.19 wt%, approximately 0.20 wt%, approximately 0.21 wt%, approximately 0.22 wt%, approximately 0.23 wt%, approximately 0.24 wt%, approximately 0.25 wt%, approximately 0.26 wt%, approximately 0.27 wt%, approximately 0.28 wt%, approximately 0.29 wt%, or approximately 0.30 wt%. The flavoring agent may be oil-soluble.

[0045] In some respects, the phosphate buffer is 100 nM phosphate buffer and the flavoring is vanilla present at a concentration of about 0.1 wt%.

[0046] In some respects, the phosphate buffer is 50 nM phosphate buffer and the flavoring is vanilla present at a concentration of about 0.2 wt%.

[0047] Tables 1 and 2 show the composition of two different emulsions.

[0048] Table 1: Emulsion 1

[0049]

[0050] Table 2: Emulsion 2

[0051]

[0052] The percentage of flavoring agent in the active ingredient or control can affect the stability of the emulsion. In some respects, reducing the percentage of flavoring agent (e.g., from about 0.2 wt% to about 0.1 wt% for the active ingredient, and from 0.4 wt% to 0.2 wt% for the control) can improve the stability of the emulsion. The concentration of phosphate buffer can also affect the stability of the emulsion. In some respects, emulsions prepared with a 100 mM buffer strength can show improved long-term stability than emulsions prepared with a 50 mM buffer strength but otherwise equivalent composition.

[0053] The emulsion may appear white to off-white, with little or no reversible phase separation. The pH of the emulsion may range from about 5.5 to about 7.5. For example, the pH may be about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5. The total aerobic microbial count of the emulsion may be less than 1000 cfu / g. The total combined count of yeasts and molds may be less than 100 cfu / g. The total impurities in the emulsion, as measured by gas chromatography, may be less than 3.5% by weight. Impurities include, but are not limited to, dicaprylic acid glyceride, dicaprylic acid monohexanoate, dicaprylic acid monoheptanoate, dicaprylic acid monononanoate, dicaprylic acid monocaprylic acid glyceride, glyceryl-tridecanoate, 1,1-diglyceryl-tetracaprylate, 1,2-diglyceryl-tetracaprylate, 2,2-diglyceryl-tetracaprylate, or combinations thereof.

[0054] Table 3 shows the release quality standards for exemplary emulsions.

[0055] Table 3: Release and Stability Quality Standards

[0056]

[0057] In some respects, emulsion formulations starting at 25°C and a pH of 6.5 are more stable. In other respects, emulsion formulations starting at 25°C and a pH of 7.8 are likely the least stable.

[0058] In some respects, emulsion formulations that start at 40°C and pH 6.5 can begin to decline after 3 months. This decline is likely due to the pH moving away from the pKa of the phosphate buffer. The results (6.8) indicate that the buffer solution is likely the most effective. In some respects, the optimal pH can be slightly higher than 6.8 to optimize pH stability and avoid the decline observed at 3 months.

[0059] In some respects, the most stable emulsion formulations can have low flavoring levels. In other respects, the most unstable emulsion formulations can have high flavoring levels.

[0060] In some respects, vanilla and berry flavored formulations can behave similarly and may not differ significantly in terms of pH stability relative to the type of flavoring.

[0061] In some respects, the most stable emulsion formulations can have high buffer strength. In other respects, the most unstable formulations can have low buffer strength. In some implementations, both buffer strength and flavoring may be important for pH stability.

[0062] Emulsion formulations with higher buffer strength, lower flavoring levels, and an initial pH of 6.8 can improve pH stability.

[0063] The following are some example lotions:

[0064] In aspect 1, an emulsion comprising the following is disclosed herein: about 20%-60% by weight of tricaprylic acid glyceride; about 0.1-10% by weight of emulsifier; about 0.1-10% by weight of glycerol; and about 10 mM-200 mM phosphate buffer (pH 6.0-7.5).

[0065] In aspect 2, the emulsion contains: approximately 50% by weight of glyceryl tricaprylate; approximately 4% by weight of Phospholipon® 90G; approximately 2% by weight of Kolliphor® RH40; approximately 2.5% by weight of glycerol; and approximately 20 mM - 100 mM phosphate buffer (pH 6.8).

[0066] In aspect 3, the emulsion contains: approximately 500 mg of tricaprylic acid glyceride; approximately 40 mg of Phospholipon® 90G; approximately 20 mg of Kolliphor® RH40; approximately 25 mg of glycerol; and approximately 415 mg of phosphate buffer (50 mM, pH 6.8), per gram of emulsion.

[0067] In aspect 4, the emulsion contains: approximately 500 mg of tricaprylic acid glyceride; approximately 40 mg of Phospholipon® 90G; approximately 20 mg of Kolliphor® RH40; and approximately 440 mg of phosphate buffer (50 mM, pH 6.8), per gram of emulsion.

[0068] In aspect 5, the emulsion contains: approximately 400 mg of tricaprylic acid glyceride; approximately 21.3 mg of Phospholipon® 90G; approximately 10.7 mg of Kolliphor® RH40; approximately 25 mg of glycerol; and approximately 543 mg of phosphate buffer (50 mM, pH 6.8), per gram of emulsion.

[0069] In aspect 6, the emulsion contains: approximately 400 mg of tricaprylic acid glyceride; approximately 32 mg of Phospholipon® 90G; approximately 16 mg of Kolliphor® RH40; and approximately 552 mg of phosphate buffer (50 mM, pH 6.8), per gram of emulsion.

[0070] In aspect 7, the emulsion contains: approximately 400 mg of tricaprylic acid glyceride; approximately 21.3 mg of Phospholipon® 90G; approximately 10.7 mg of Kolliphor® RH40; and approximately 568 mg of phosphate buffer (50 mM, pH 6.8), per gram of emulsion.

[0071] In aspect 8, the emulsion contains: approximately 400 mg of tricaprylic acid glyceride; approximately 32 mg of Phospholipon® 90G; approximately 16 mg of citrem; approximately 25 mg of glycerol; and approximately 527 mg of phosphate buffer (50 mM, pH 7), per gram of emulsion.

[0072] In aspect 9, the emulsion contains: approximately 200 mg of tricaprylic acid glyceride; approximately 16 mg of Phospholipon® 90G; approximately 8 mg of Kolliphor® RH40; approximately 25 mg of glycerol; and approximately 751 mg of phosphate buffer (50 mM, pH 6.8), per gram of emulsion.

[0073] In aspect 10, the emulsion contains: approximately 200 mg of tricaprylic acid glyceride; approximately 24 mg of Phospholipon® 90G; approximately 2 mg of Kolliphor® RH40; approximately 5 mg of sodium oleate; approximately 25 mg of glycerol; and approximately 744 mg of phosphate buffer (50 mM, pH 8.0), per gram of emulsion.

[0074] In aspect 11, the emulsion contains: approximately 400 mg of tricaprylic acid glyceride; approximately 32 mg of Phospholipon® 90G; approximately 16 mg of Kolliphor® RH40; approximately 25 mg of glycerol; and approximately 527 mg of phosphate buffer (50 mM, pH 6.8), per gram of emulsion.

[0075] In aspect 12, the emulsion contains: approximately 200 mg of tricaprylic acid glyceride; approximately 16 mg of Phospholipon® 90G; approximately 8 mg of Kolliphor® RH40; and approximately 776 mg of phosphate buffer (50 mM, pH 6.8), per gram of emulsion.

[0076] In aspect 13, the emulsion of any one of aspects 1-12 further comprises: 0.1% to about 1% by weight of a sweetener, wherein the amount of phosphate buffer in grams is reduced taking into account the amount of the added sweetener.

[0077] In aspect 14, the emulsions of aspects 1-13 further include: 0.1%-0.3% flavoring agent, wherein the amount of phosphate buffer (in grams) is reduced taking into account the amount of flavoring agent added.

[0078] In aspect 15, the emulsion contains: approximately 500 mg of caprylic acid glyceride; approximately 40 mg of Phospholipon® 90G; approximately 20 mg of Kolliphor® RH40; approximately 25 mg of glycerol; approximately 0.5 mg of sucralose; approximately 2 mg of vanilla flavoring; and approximately 412.5 mg of phosphate buffer (50 mM, pH 6.8), per gram of emulsion.

[0079] In aspect 16, the emulsion contains: approximately 500 mg of caprylic acid glyceride; approximately 40 mg of Phospholipon® 90G; approximately 20 mg of Kolliphor® RH40; approximately 25 mg of glycerol; approximately 0.5 mg of sucralose; approximately 1 mg of vanilla flavoring; and approximately 413.5 mg of phosphate buffer (100 mM, pH 6.8), per gram of emulsion.

[0080] In aspect 17, the emulsion contains: approximately 500 mg of caprylic acid glyceride; approximately 40 mg of Phospholipon® 90G; approximately 20 mg of Kolliphor® RH40; approximately 25 mg of glycerol; approximately 0.5 mg of sucralose; approximately 1 mg of vanilla flavoring; and approximately 413.5 mg of phosphate buffer (50 mM, pH 7.0), per gram of emulsion.

[0081] II. Methods for preparing emulsion formulations

[0082] This disclosure also relates to a method for preparing an emulsion, which may include tricaprylic acid glyceride. The method includes feeding a buffer solution, tricaprylic acid glyceride, and one or more emulsifiers into a container; mixing the phosphate buffer solution, tricaprylic acid glyceride, and one or more emulsifiers in the container under high shear to form a crude emulsion; sterilizing the crude emulsion to obtain a sterile emulsion; and high-pressure homogenizing (HPH) the sterile emulsion to form an emulsion containing tricaprylic acid glyceride. In some aspects, sterilizing the emulsion may include, consist of, or exclude: an irradiation process, such as gamma radiation or X-ray irradiation. In some aspects, the sterilization process may include, consist of, or exclude: ultra-high temperature (UTH) treatment.

[0083] Figure 1-3 Figures 7, 9, and 11 illustrate some methods for preparing the emulsions of this disclosure. A first step of the method includes high-shear mixing of a phosphate buffer, glyceryl tricaprylate, and one or more emulsifiers in a container to form a crude emulsion. In some aspects, high-shear mixing can be achieved by adding water and sodium dihydrogen phosphate dihydrate to the container. The pH of the container can be adjusted to approximately 6.8 using about 2M sodium hydroxide solution. Next, one or more emulsifiers can be added to the phosphate buffer. In some aspects, an alcohol can be added to the phosphate buffer. The alcohol can be a triol. In some aspects, the triol can be glycerol. An active pharmaceutical ingredient or a control ingredient can be added to the container. The mixture can be mixed online at about 10,000 rpm by high-shear mixing or by a top-of-the-line high-shear mixer to obtain a crude emulsion. The temperature at which high-shear mixing can be performed is in the range of about 15°C to about 45°C. The particle size of the resulting crude emulsion can be from about 1 µm to about 10 µm. In some aspects, the particle size can be in the range of about 1 µm to about 5 µm.

[0084] In some aspects, the next step of the method may include a sterilization step. In some aspects, the sterilization step is an ultraheat treatment (UHT) step. UHT conditions may include heating the crude mixture at a temperature of about 125°C to about 150°C for about 5 seconds to about 60 seconds. In some aspects, the temperature may be about 125°C to about 130°C, about 130°C to about 135°C, about 135°C to about 140°C, about 140°C to about 145°C, or about 145°C to about 150°C. In some aspects, the duration may be about 5 seconds to about 10 seconds, about 10 seconds to about 15 seconds, about 15 seconds to about 20 seconds, about 20 seconds to about 25 seconds, about 25 seconds to about 30 seconds, about 30 seconds to about 35 seconds, about 35 seconds to about 40 seconds, about 40 seconds to about 45 seconds, about 45 seconds to about 50 seconds, about 50 seconds to about 55 seconds, or about 55 seconds to about 60 seconds. In some aspects, the UHT treatment is performed at 135°C for 2.35 seconds. In some aspects, the UHT treatment is performed at 135°C for 5 seconds.

[0085] In some aspects, the next step of the method includes high-pressure homogenization (HPH) superheating treatment of the crude emulsion to form a fine emulsion. In some aspects, the high pressure can be between 5,000 PSI and about 10,000 PSI. In some aspects, the high pressure can be at least 5,000, at least 5,500, at least 6,000, at least 6,500, at least 7,000, at least 7,500, at least 8,000, at least 8,500, at least 9,000, at least 9,500, or at least 10,000 PSI. In some aspects, the high pressure can be about 7,500 PSI. The particle size of the fine emulsion can be in the range of about 0.05 µm to about 1 µm. In some aspects, the particle size of the fine emulsion can be less than 0.4 µm. HPH can be performed once or multiple times until the desired particle size is achieved. For example, the number of HPH passes can be from 1 to about 10³.

[0086] In some respects, the final step of the method involves filling the fine emulsion into suitable glass vials. These vials include, but are not limited to, 30 mL or 100 mL amber glass bottles. In some respects, the vials may be filled in a biocabinet to avoid microbial contamination. In some respects, the emulsion may be subjected to gamma irradiation. In other respects, gamma irradiation may not be performed on the emulsion. Gamma irradiation may negatively affect the taste of the resulting emulsion.

[0087] In some respects, glass vials can be filled under laminar flow. In some respects, the vials and caps can be subjected to gamma radiation, and glass vials can be filled in a biological cabinet. In some respects, the vials and caps can be subjected to gamma radiation, and glass vials can be filled under laminar flow.

[0088] In some aspects, the method also includes adding one or more sweeteners and / or flavoring agents during the manufacturing process; in some aspects, the one or more sweeteners and / or flavoring agents may be added at any step during the manufacturing process. In some aspects, one or more sweeteners and / or flavoring agents may be added during or before a feeding step, a high-shear mixing step, or a high-pressure homogenization step. In some aspects, one or more sweeteners and / or flavoring agents may be added before a bottling step. In such aspects, the one or more sweeteners and / or flavoring agents may be sterilized independently.

[0089] III. Methods of using emulsions

[0090] In some aspects, this disclosure relates to methods for treating a disease or disorder in a subject in need, the method comprising administering to the subject a pharmaceutical composition of this disclosure in an amount that effectively increases the concentration of ketone bodies in the subject, thereby treating the disease or disorder. In some aspects, the pharmaceutical compositions of this disclosure can be administered outside of a ketogenic diet setting. For example, in the context of this disclosure, carbohydrates can be consumed concurrently with the pharmaceutical compositions disclosed herein.

[0091] According to certain aspects of this disclosure, the disorder is a neurological disease or disorder, such as a disease associated with cognitive decline, decreased neuronal metabolism, or infantile spasms.

[0092] In some respects, diseases and disorders can include those associated with cognitive decline; for example, age-related memory disorder (AAMI), Alzheimer's disease (AD), Parkinson's disease, Friedreich ataxia (FRDA), GLUT1-deficient epilepsy, dwarfism syndrome, Rabson-Mendenhall syndrome, coronary artery bypass graft (CABG) dementia, anesthesia-induced memory loss, Huntington's disease, migraines, and related headaches. On the other hand, patients have or are at risk of developing cognitive decline associated with diseases caused by decreased neuronal metabolism, such as cognitive decline associated with Alzheimer's disease (AD), Parkinson's disease, Friedreich ataxia (FRDA), GLUT1-deficient epilepsy, dwarfism syndrome, Rabson-Mendenhall syndrome, coronary artery bypass graft (CABG) dementia, anesthesia-induced memory loss, and Huntington's disease.

[0093] As used in this article, 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, production of reactive oxygen species (ROS), ROS-induced neuronal apoptosis, defects in glucose transport or glycolysis, membrane ion potential imbalance, and calcium flux dysfunction.

[0094] According to the present invention, high blood ketone levels will provide an energy source for brain cells with impaired glucose metabolism, leading to improved cognitive function. As used herein, "subject" and "patient" are used interchangeably and refer to any mammal, including humans, that may benefit from treatment of diseases and conditions associated with or caused by decreased neuronal metabolism.

[0095] "Effective quantity" refers to the quantity of a compound, material, or pharmaceutical composition as described herein that effectively achieves a specific biological outcome. The effectiveness of treatment for the aforementioned conditions can be assessed by improved results from at least one neuropsychological test. These neuropsychological tests are known in the art and include the Clinical Global Change Impression (CGIC), Ray's Auditory Verbal Learning Test (RAVLT), First Name-Surname Association Test (FLN), Telephone Dialing Test (TDT), Clinical Self-Rating Memory Assessment Scale (MAC-S), Symbolic Digit Coding (SDC), SDC Delayed Recall Task (DRT), Distraction Attention Test (DAT), Visual Sequence Comparison (VSC), DAT Dual Task (DAT Dual), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS), among others.

[0096] The term “cognitive function” refers to specific, normal, or appropriate physiological activities of the brain, including but not limited to at least one of the following: mental stability, memory / recall ability, problem-solving ability, reasoning ability, thinking ability, judgment ability, learning ability, perception, intuition, attention, and consciousness.

[0097] "Enhanced cognitive function" or "improved cognitive function" refers to any improvement in the brain's specific, normal, or appropriate physiological activity, including, but not limited to, at least one of the following: mental stability, memory / recall ability, problem-solving ability, reasoning ability, thinking ability, judgment ability, learning ability, perception, intuition, attention, and awareness, as measured by any appropriate method in the art. "Decreased cognitive function" or "impaired cognitive function" refers to any decline in the brain's specific, normal, or appropriate physiological activity.

[0098] In another aspect, the method of the present invention further includes determining the patient's genotype or specific allele. In one aspect, the allele of the apolipoprotein E gene in the patient is determined. It has been found that non-E4 carriers perform better than carriers with the E4 allele when elevated ketone body levels are induced with MCT. Furthermore, those with the E4 allele have higher fasting ketone body levels and the levels continue to rise at two-hour intervals. Therefore, E4 carriers may require higher ketone levels or reagents with increased capacity to utilize existing ketone bodies.

[0099] In one aspect, the pharmaceutical composition of this disclosure is administered orally. The therapeutically effective amount of the therapeutic agent can be any amount or dose sufficient to produce the desired effect, and depends in part on the severity and stage of the condition, the size and condition of the patient, and other factors readily known to those skilled in the art. The dosage can be administered as a single dose or as several doses, for example, in divided doses over several weeks, as discussed elsewhere herein.

[0100] In one aspect, the pharmaceutical compositions of this disclosure are administered at the dose required to increase blood ketone bodies to the level necessary for treating and / or preventing the occurrence of any disease or age-related cognitive decline, such as AD, AAMI, etc. A suitable dose can be determined by those skilled in the art.

[0101] In one aspect, oral administration of the pharmaceutical composition of this disclosure results in hyperketosis. In another aspect, hyperketosis causes ketone bodies to be used for energy in the brain even in the presence of glucose.

[0102] In addition, hyperketonemia leads to 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 (Veneman, T. et al., 1996, 270:E746-51). It has been reported that in normal individuals, hyperketonemia reduces cognitive dysfunction associated with systemic hypoglycemia (Veneman, T. et al., Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans). Diabetes (1994, 43:1311-7). Please note that systemic hypoglycemia is different from localized defects in glucose metabolism that occur in any disease or age-related cognitive decline, such as AD, AAMI, etc.

[0103] Application can be based on need or expectation, such as once a month, once a week, daily, or more than once a day. Similarly, it can be applied every other day, week, or month; every three days, week, or month; every four days, week, or month, etc. It can be applied multiple times a day. When used as a supplement to normal dietary needs, the composition can be applied directly to the patient or otherwise mixed with or taken from their daily feed or food.

[0104] In one respect, the pharmaceutical compositions presented herein are intended for “long-term” consumption, sometimes referred to herein as “extended time period”.

[0105] As used in this article, “long-term” application usually refers to a period of time exceeding one month.

[0106] A period of time longer than two months, three months, or four months is included in one aspect of the invention. It also includes aspects that include longer periods of time, such as five, six, seven, eight, nine, or ten months. Periods exceeding 11 months or one year are also included. Long-term use lasting one, two, three, or more years is also contemplated herein.

[0107] As used herein, “regularly” means administering or consuming the composition at least once a week. This includes more frequent administration or consumption, such as twice or three times a week. It also includes regimens that include consumption at least once a day. Those skilled in the art will understand that the blood level of ketone bodies or a particular ketone body achieved can be a valuable measure of the frequency of administration. Any frequency that allows the blood level of the measured compound 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 some compositions may require administration more or less frequently to maintain the desired blood level of the measured compound (e.g., ketone bodies).

[0108] Administration can be performed periodically, for example, as part of a patient's treatment regimen. The treatment regimen may include the regular ingestion of a pharmaceutical composition of this disclosure that effectively enhances the patient's cognitive function, memory, and behavior.

[0109] Regular intake can be once a day, or twice, three times, four times or more a day, based on daily or weekly intake.

[0110] Similarly, regular administration can be every other day or week, every three days or week, every four days or week, every five days or week, or every six days or week, and in such regimens, administration can be multiple times a day. The purpose of regular administration is to provide the patient with the optimal dose of the pharmaceutical composition of this disclosure, as illustrated herein.

[0111] The disclosed compositions (e.g., those containing MCT) can be administered in an effective amount to increase cognitive function in patients with diseases of decreased neuronal metabolism, such as in patients with any disease or age-related cognitive decline such as AD, AAMI, etc.

[0112] In one aspect, the disclosed composition results in an increase in ketone concentration in the body, and in that aspect, the composition is administered in an amount that effectively induces hyperketosis. In another aspect, hyperketosis causes ketone bodies to be used for energy in the brain.

[0113] In one aspect, the composition increases the circulating concentration of at least one type of ketone body in mammals or patients. In one aspect, the circulating ketone body is D-β-hydroxybutyrate. The amount of circulating ketone body can be measured multiple times after administration, and in one aspect, at a time when the predicted peak concentration in the blood is expected, but also before or after the predicted peak blood concentration level. The amounts measured at these non-peak times are then optionally adjusted to reflect the predicted level at the predicted peak time. In one aspect, the predicted peak time is about two hours. The peak circulating blood level and time can vary according to factors known to those skilled in the art, including individual digestibility, co-ingestion of food or beverage, or pre- or post-ingestion, as known to those skilled in the art. In one aspect, the peak blood level reached by D-β-hydroxybutyrate is between about 0.05 mmol (mM) and about 50 mM. Another method for determining whether the blood level of D-β-hydroxybutyrate has increased to about 0.05 to about 50 mM is by measuring the range of D-β-hydroxybutyrate urinary excretion in the range of about 5 mg / dL to about 160 mg / dL. In other respects, peak blood levels are increased 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, more preferably to about 0.15 to about 2 mM, about 0.15 to about 0.3 mM and about 0.2 to about 5 mM, although these will necessarily vary depending on the formulation and the host, as discussed above. In other respects, the peak blood levels reached by D-β-hydroxybutyric acid 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.

[0114] The effective amount of the compound used in the disclosed compositions, i.e., a compound capable of increasing ketone body concentration to an amount that effectively treats or prevents cognitive loss caused by decreased neuronal metabolism, will be apparent to those skilled in the art. As discussed above, such an effective amount can be determined based on the disclosed blood ketone levels. When the compound capable of increasing ketone body concentration is MCT, in one aspect, the MCT dose is in the range of about 0.05 g / kg / day to about 10 g / kg / day. In other aspects, the dose will be in the range of about 0.25 g / kg / day to about 5 g / kg / day. In other aspects, the dose will be in the range of about 0.5 g / kg / day to about 2 g / kg / day. In other aspects, the dose will be in the range of about 0.1 g / kg / day to about 2 g / kg / day. In other respects, the dosage of MCT is at least about 0.05 g / kg / day, at least about 0.1 g / kg / day, at least about 0.15 g / kg / day, at least about 0.2 g / kg / day, at least about 0.5 g / kg / day, at least about 1 g / kg / day, at least about 1.5 g / kg / day, at least about 2 g / kg / day, at least about 2.5 g / kg / day, at least about 3 g / kg / day, at least about 4 g / kg / day, at least about 5 g / kg / day, at least about 10 g / kg / day, at least about 15 g / kg / day, at least about 20 g / kg / day, at least about 30 g / kg / day, at least about 40 g / kg / day, and at least about 50 g / kg / day.

[0115] As described herein, the compositions of the present invention are provided as liquid formulations for administration to subjects in need. The compositions can be advantageously used in combination and / or in combination with other therapeutic or preventative agents different from the disclosed MCT compounds. In many cases, co-administration with the subject composition enhances the efficacy of such agents. For example, the compounds can be advantageously used in combination with antioxidants, compounds that improve glucose utilization, and mixtures thereof

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

[0116] IV. Terminology

[0117] The wording and terminology used herein are for descriptive purposes and should not be considered restrictive. For example, the use of singular terms such as “a / a” is not intended to limit the number of items. Furthermore, for clarity, the use of relational terms such as, but not limited to, “top,” “bottom,” “left,” “right,” “upper,” “lower,” “under,” “above,” and “side” in the description with specific reference to the accompanying drawings is not intended to limit the scope of this disclosure or the appended claims.

[0118] Any degree term, such as "substantially" as used in, but not limited to, the specification and appended claims, should be understood to include precise or similar, but not precise, configurations. For example, "substantially flat surface" means having a precisely flat surface or a similar, but not precisely flat surface. Similarly, the terms "about" or "approximately" as used in the specification and appended claims should be understood to include values ​​that are three times or one-third of the stated value. For example, about 3 mm includes all values ​​from 1 mm to 9 mm, and about 50 degrees includes all values ​​from 16.6 degrees to 150 degrees. For example, they may refer to less than or equal to ±5%, such as less than or equal to ±2%, such as less than or equal to ±1%, such as less than or equal to ±0.5%, such as less than or equal to ±0.2%, such as less than or equal to ±0.1%, such as less than or equal to ±0.05%.

[0119] In this disclosure, the terms “comprising,” “including,” and “having” are used interchangeably. The terms “comprising,” “including,” and “having” mean to include, but not necessarily to limit, the things described.

[0120] As used herein, the terms “or” and “and / or” should be interpreted as inclusive or referring to any one or any combination thereof. Therefore, “A, B, or C” or “A, B, and / or C” means any of the following: “A,” “B,” or “C”; “A and B”; “A and C”; “B and C”; “A, B, and C”. Exceptions to this definition will only occur if the combination of elements, functions, steps, or actions is inherently mutually exclusive in some way.

[0121] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains. The following references provide general definitions for many of the terms used herein: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd edition, 1994); The Cambridge Dictionary of Science and Technology (Walker, ed., 1988); The Glossary of Genetics, 5th edition, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991), all of which are incorporated herein by reference. As used herein, unless otherwise stated, the following terms have the meanings assigned to them as follows.

[0122] The wording and terminology used herein are for descriptive purposes and should not be considered restrictive. When describing elements of this disclosure or preferred aspects thereof, the articles “a,” “an,” “the,” and “described” are intended to indicate the presence of one or more elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that additional elements may be present besides those listed. Wherever the terms “comprising” or “including” are used, it should be understood that this disclosure also expressly contemplates and covers additional aspects “composed” of the disclosed elements, excluding elements other than those listed.

[0123] As used herein, the terms “about” or “approximately” can mean within an acceptable margin of error for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as limitations of the measuring system. For example, “about” can mean within one or more standard deviations of a given value, as is customarily stated. Where a particular value is described in this application and claims, unless otherwise stated, the term “about” can mean an acceptable margin of error for the particular value, such as 10% of the value modified by the term “about”. As used herein, the term “about” can mean ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% relative to the value, such as amount, dose, temperature, time, percentage, etc.

[0124] Furthermore, because this disclosure is susceptible to influence by many different aspects, it is intended to be regarded as an example of the principles of this disclosure and not as limiting it to the specific aspects shown and described. Any feature of this disclosure may be used alone or in combination with any other feature. References to the terms "(one / more) aspects," etc., in the specification mean that one and / or more features mentioned are included in at least one aspect of the specification. Unless stated as such and / or apparent from the specification by a person skilled in the art, individual references to the terms "(one / more) aspects," etc., in the specification do not necessarily refer to the same aspects and are not mutually exclusive. For example, features, structures, processes, steps, actions, etc., described in one aspect may be included in other aspects, but are not necessarily included. Therefore, this disclosure may include various combinations and / or integrations of the aspects described herein. Additionally, all aspects of this disclosure as described herein are not essential for its practice. Similarly, other systems, methods, features, and advantages of this disclosure will be or become apparent to a person skilled in the art upon examination of the drawings and specification. All such additional systems, methods, features, and advantages are intended to be included within the scope of this specification, the disclosure, and the claims.

[0125] As will be appreciated by those skilled in the art from the detailed description, the accompanying drawings and the claims, modifications and changes may be made to aspects of this disclosure without departing from the scope of this disclosure as defined by the appended claims.

[0126] Example

[0127] The following examples illustrate various non-limiting aspects of this disclosure.

[0128] Example 1: Development of a basic emulsion formulation of tricaprylic acid glyceride

[0129] Table 4 provides a list of basic formulations developed for clinical research. These formulations are... Figure 1Prepared using the general methods outlined in the table, and without any flavoring agents. The gamma irradiation protocol was used to reduce biological load. Refer to Table 4: Phospholipon® 90G is lecithin supplied by Lipoid and contains at least 94% phosphatidylcholine as the main ingredient; Kolliphor® RH40 is the trade name for polyoxyethylene 40 hydrogenated castor oil (USP), also known as polyethylene glycol glycerol hydroxystearate; glycerol is also known as glycerol; the formal name for citrem is citrate of monoglyceride and diglyceride; a 50 mM phosphate buffer at pH 6.8 was prepared by mixing 7.8 mg / mL sodium dihydrogen phosphate dihydrate USP / Ph.Eur with low-temperature raw water (Baxter Water for Irrigation); the pH was then adjusted with 2 M sodium hydroxide NF / BP.

[0130] Table 4: Unflavored Emulsion Formulations

[0131]

[0132] These formulations were used in clinical trials. However, comments from clinical trial participants made it necessary to improve the taste of the emulsions. Taste assessments showed that gamma irradiation might have a negative impact on the taste of the formulations. Therefore, studies were conducted to develop flavored versions of several lead formulations. AC-OLE-1 and AC-OLE-03 were used in subsequent trials.

[0133] Example 2: Optimization of sweetness and flavoring

[0134] Based on the initial input, several flavorings were shortlisted. These included vanilla, mango, and / or berries. In addition to the flavoring agents, various sweeteners were tested. Two sweeteners were considered for further testing: sucralose and stevia (see Table 6). The composition of the base formulations used to add flavorings and sweeteners is summarized in Table 5 below.

[0135] Table 5: Composition of the basic formulation used for flavoring optimization research

[0136]

[0137] The sweetener concentrations were evaluated in the three separate trials listed in Table 6:

[0138] Table 6: Sweeteners and Concentrations Used for Selecting Sweetener Levels and Types

[0139]

[0140] Formulations were prepared using the sweetener concentrations detailed in Table 6 and 0.3% Givaudan vanilla. No significant difference was found between sucralose and stevia. Sucralose was chosen as the sweetener for further testing because it can be used at lower concentrations, and 0.05% was selected for another study. Furthermore, the Givaudan vanilla concentration was halved for another study because it was found to be too strong in this experiment.

[0141] Five vanilla flavorings from three different companies were screened. Sample AC-OLE-03 was studied to compare flavorings and determine preferred options. Concentrations were selected based on manufacturer recommendations and an initial test with sucralose set at 0.05%, as recommended in previous sweetener selection studies. The flavoring agents tested are detailed in Table 7.

[0142] Table 7: Details of the flavoring agent screening experiment

[0143]

[0144] Oil-soluble flavorings were determined to have a more balanced flavor and a reduced aftertaste. Sensient® Vanilla 2 (also known as Strong Vanilla Flavoring, hereinafter referred to as Vanilla Flavoring or Vanilla) was selected at a concentration of 0.2%. Alternative flavoring options were also identified, including mango and berry flavorings. Four mango flavorings were used. A study was conducted on sample AC-OLE-03 to (i) compare the flavorings with the supplied berry flavorings, and (ii) determine the preferred selection. Overall, the mango flavorings did not taste good. Scentral Mango 1 was considered the best. However, the berry flavorings were superior to all the mango flavorings and were recommended as an alternative flavoring at a concentration of 0.3%.

[0145] During the flavoring agent selection study, formulation AC-OLE-01, with higher concentrations of both oil and emulsifier, was also tested. AC-OLE-01 active ingredient and placebo samples were flavored and tasted at the optimized concentrations detailed in Table 8. In all cases, the flavored samples were acceptable and comparable to the AC-OLE-03 equivalent. However, the AC-OLE-01 samples had a creamier / thicker mouthfeel.

[0146] Table 8: Summary of active substances that match flavor

[0147]

[0148] In addition, it was determined that the formulations tested so far were too sweet and had an overly strong vanilla flavor. Therefore, formulations with reduced sweetness were tested. Table 9 below lists the tested formulations with reduced sweetness.

[0149] Table 9: Preparations with reduced vanilla and sweetness

[0150]

[0151] Based on these studies, formulation 5 was selected as the optimal option as the third formulation with a lower vanilla flavor and sucralose concentration. Typically, a minimum of 0.015% sucralose was observed, along with a balance of flavoring and sweeteners to achieve the best properties for each component.

[0152] In addition to these studies, flavor optimization was tested on several other samples. The observations and conclusions of these studies are summarized below.

[0153] Example 3: Effects of γ-ray and X-ray irradiation on seasoning

[0154] The initial protocol used to manufacture the tricaprylic acid glyceride formulation employed gamma irradiation to reduce bioburden. Therefore, the effect of this process on flavor was evaluated. The first study involved flavoring previously irradiated AC-OLE-03 samples with a lead vanilla flavoring agent. Concentrations of vanilla up to 0.5% and sucralose up to 0.2% were used. In all cases, both flavored and unflavored AC-OLE-03 samples tasted poor due to the “cooked” / off-flavor imparted by irradiation.

[0155] The next study focused on irradiating flavored AC-OLE-03 samples to determine whether the presence of flavoring during this process could suppress / mask the production of unpleasant off-flavors. Stevia and sucralose were used along with vanilla, berry, and lemon-lime flavorings. In all cases, the flavor after irradiation was poor, and in some cases, minimal traces of the flavoring agents were retained. Therefore, alternative approaches focusing on reducing bioburden are recommended.

[0156] One of the alternative bioburden reduction methods evaluated was X-ray irradiation. This provides the ability to irradiate with a lower total dose. X-ray irradiation doses of 2 kGy and 5 kGy were compared to a gamma irradiation dose of 10 kGy. A range of vanilla and berry flavors were tested for both AC-OLE-01 and AC-OLE-03 formulations. The culinary flavor persisted in these formulations, although slightly diminished in those treated with both X-ray irradiation doses. Bioburden reduction methods other than irradiation-based approaches were tested in subsequent formulations. In some cases, shelf life and flavor of formulations without any bioburden reduction treatment were also tested.

[0157] Example 4: Conclusions from a flavoring optimization study

[0158] Extensive studies were completed to identify suitable combinations of flavoring and sweeteners for oral emulsion products. In summary, based on these studies, the recommended lead and backup formulations are:

[0159] Lead active formulation: 0.2% vanilla, 0.05% sucralose (see Table 10 for complete formulation details)

[0160] Alternative active ingredients: 0.3% berries, 0.05% sucralose

[0161] Acceptable flavor formulations were also produced using reduced concentrations of vanilla (0.1%) and sucralose (0.015% and 0.025%). Adding the same concentrations of sweetener and flavoring agent to both AC-OLE-01 and AC-OLE-03 formulations produced comparable flavor results. Flavorings produced by gamma and X-ray irradiation could not be adequately masked by the added flavoring agent.

[0162] Table 10: Active formulation of lead vanilla flavoring (AC-OLE-01-VA)

[0163]

[0164] Example 5: The process of adding flavorings and sweeteners and the effect of nitrogen headspace.

[0165] After optimizing the type, supplier, and concentration of flavorings and sweeteners, the flavoring addition process was considered. Two different addition points were considered, such as... Figure 2 As shown in the diagram. The first addition point is at the beginning of the process, before adding the oil to the buffer and emulsifier mixture, by mixing the oil-soluble vanilla flavoring with the tricaprylic acid glyceride oil. This process is considered preferred because the flavoring will mix well with the oil. Controlling the bioload is also easier compared to adding the flavoring later in the process. However, if added at the beginning and thus throughout the entire manufacturing process, it is questionable whether the flavoring will be affected. The second addition point is near the end of the process, after high-pressure homogenization and just before filling. The advantage of this addition point is that the flavoring has not been subjected to the preceding manufacturing processes, thus it is expected that the flavoring will not change. A potential disadvantage would be that mixing the oil-soluble flavoring with the emulsion oil droplets in a uniform manner would be challenging, potentially affecting emulsion stability. Furthermore, adding the flavoring at the end of the process without potentially affecting the bioload could be challenging.

[0166] To investigate the optimal addition point, laboratory studies were conducted, including:

[0167] a) At the beginning of this method, the vanilla flavoring agent is mixed with glyceryl tricaprylate until visibly homogeneous. In this method, sucralose sweetener is mixed with buffer and emulsifier at the beginning of the method.

[0168] b) At the end of the method, add the vanilla flavoring and sucralose sweetener. This is done by adding the flavoring and sucralose to 450g of high-pressure homogenized emulsion in a 1-liter beaker and mixing at 750rpm with a top stirrer equipped with a 60mm diameter propeller impeller.

[0169] It was observed that the oil-soluble vanilla flavoring was readily dispersed in caprylic / capric triglycerides with minimal stirring. When sucralose and vanilla flavoring were added at the end of method (method b), they dispersed very rapidly, forming a homogeneous emulsion. Vanilla flavoring (Intense Vanilla, Sensient® product code: QAA0016060002 / AA000851015) was introduced at 0.2% (w / w) in all cases, and sucralose sweetener (KANBOSWEET) was introduced at 0.05% (w / w).

[0170] To investigate the effect of nitrogen headspace, some sample containing vanilla and sucralose was added to glass vials at the start of the process, and the uncapped vials and caps were transferred to a glove bag attached to the nitrogen cylinder. The bag was purged three times with nitrogen, and then the vials were capped inside the bag. Once removed from the bag, Teflon tape was wrapped around the edges of the vials to seal them and prevent air from penetrating into the sample.

[0171] The formulations prepared by different methods were filled into 30 mL amber glass bottles and placed stably.

[0172] When comparing data on color, pH, particle size, assays, and related substances up to 2 months, no significant difference was confirmed between adding the flavoring agent at the beginning (first addition) and the end (later addition) of the method. This indicates that there is no difference in these key physicochemical parameters regardless of whether the flavoring agent is added at the beginning or the end of the method.

[0173] A small difference was observed in the results for the active formulation (formulation-first addition method, N2 headspace) after nitrogen packing compared to the samples not packed under nitrogen, as some impurities were present at slightly higher levels in the N2 headspace samples at the 1-month time point at 25°C and the 2-month time point at 2–8°C. However, the difference was small, and nitrogen headspace seemed unlikely to generate more impurities, and therefore unlikely to be meaningful.

[0174] Example 6: Taste testing of samples prepared using pre- or post-addition methods and nitrogen headspace.

[0175] To examine whether the addition and filling points under nitrogen atmosphere affected the taste, taste tests were conducted at the initial (T0) and 1-month time points. A triangular taste test method was used. Each tasting group tasted three samples, each consisting of two from one sample and one from another, and attempted to identify the odd-numbered samples. Results at the initial time point indicated that the point of flavoring addition did not significantly affect the taste of the samples.

[0176] A similar triangular taste test was conducted at the one-month time point, and the results are shown in Table 8. At this time point, were the test panel members able to distinguish the differences between the following samples:

[0177] a) Both the active substance added to the sample first and the active substance added to the sample later were stored at 25℃.

[0178] b) For active substances stored at 25°C, add the sample first; for active substances stored at 2-8°C, add the sample last.

[0179] c) Both the active material added first sample and the active material added first sample under nitrogen atmosphere were stored at 25℃.

[0180] d) The active substance stored at 25℃ was first added to the sample along with the freshly prepared sample of the active substance.

[0181] No significant differences were identified between samples added first and last, stored at 2–8°C, filled under nitrogen or ambient air, or between samples one month old and freshly prepared, indicating that none of these factors significantly affected the taste at the one-month time point. It is possible that differences might appear at later time points; however, the insignificant differences after one month suggest that any differences that might appear later are likely minor.

[0182] The overall conclusion is that adding flavoring agents at the beginning or end of the method or filling under nitrogen has no significant effect on the physicochemical properties of the active or placebo formulation, nor on the taste up to 1 month.

[0183] Based on these results, it is therefore recommended to mix the seasoning with the oil at the beginning of the method, such as... Figure 3 As illustrated in the diagram, it is more certain that the flavoring will mix more evenly among the different oil droplets in the final emulsion, and the bioload is easier to control compared to adding the flavoring at the end of the process.

[0184] Example 7: Detailed Manufacturing Method

[0185] Preparation of 2 M NaOH

[0186] Transfer the low-heat source water to a suitable beaker. Weigh an appropriate amount of sodium hydroxide into a suitable container. Transfer the sodium hydroxide to the beaker containing the low-heat source water and stir using a top-mounted stirrer equipped with a stainless steel stirrer until all the sodium hydroxide has dissolved.

[0187] Preparation of 50mM phosphate buffer at pH 6.8

[0188] Weigh sodium dihydrogen phosphate dihydrate into a suitable container. Weigh the low-heat source water into a stainless steel mixing tank. Add the sodium dihydrogen phosphate dihydrate to the low-heat source water and stir until all the sodium dihydrogen phosphate dihydrate is dissolved. Adjust the pH of the solution to 6.8 (target value ± 0.1) using the 2 M NaOH prepared above. Stir the solution for less than 1 minute after each addition of sodium hydroxide solution.

[0189] Emulsion preparation

[0190] Warm Kolliphor® RH40 in an oven to 60°C or lower. While Kolliphor® is melting, manually stir the material for at least 2 minutes, then weigh it into phosphate buffer and begin mixing using a stainless steel stirrer. Weigh glycerol into the appropriate container and transfer it to the Kolliphor® RH40 solution in phosphate buffer. Weigh sucralose into the appropriate container and transfer it to the Kolliphor® RH40 / glycerol solution in phosphate buffer. Weigh 90g of Phospholipon® and add it to the sucralose / Kolliphor® RH40 / glycerol solution. Stir the solution for 15 minutes.

[0191] Prepare the oil and flavoring mixture. Weigh either caprylic / capric triglyceride (active) or safflower oil (control) in separate containers. Weigh the strong vanilla flavoring and add it to the container. Add the vanilla flavoring along with the caprylic / capric triglyceride or safflower oil to the container. Mix the mixture for 5 minutes.

[0192] Add the oil and flavoring mixture to a Phospholipon® 90G / sucralose / Kolliphor® RH 40 / glycerol solution in phosphate buffer to form a bulk solution.

[0193] An online high-shear emulsifier was set up and connected to a stainless steel mixing tank containing the bulk solution. The bulk solution was fed through the emulsifier into a 30L stainless steel receiving tank. The bulk solution was manually stirred in the receiving tank, and the temperature was measured. The bulk solution was fed twice into the online high-shear emulsifier. The temperature of the bulk solution was maintained at 40°C. Samples were removed during the process, and the particle size was measured until the particle size (d(0.5)) was below 5µm. The actual particle size was 2.853µm, thus forming a coarse emulsion.

[0194] An EmulsiFLEX-C55® (Avestin) high-pressure homogenizer was set up to homogenize the contents of the tank. The crude emulsion was homogenized at 10,000 PSI in a 50L tank and then transferred to another tank. The high-pressure homogenization between tanks was repeated multiple times, and a total of 2-5 times depending on the batch. The tank setup is listed in Table 11 below. Samples were measured during the process to check the particle size during high-pressure homogenization. The process was continued until a particle size (d(50)) of less than 0.4 µm was obtained. The measured particle size d(0.5) was 0.133 µm, yielding a fine emulsion.

[0195] Table 11

[0196]

[0197] The fine emulsion was filled into 100 mL amber glass containers with screw caps. The amber bottles had been pre-sterilized by gamma irradiation.

[0198] Examples of particle size distribution measurements taken during laboratory-scale formulation development for the lead active formulation AC-OLE-01-VA (0.2% strong vanilla flavoring, 0.05% sucralose) are shown below. Figure 4 In. Figure 4 In the figure, the top particle size distribution represents the measurement taken after high-shear mixing, and the bottom particle size distribution represents the measurement taken after seven passes of high-pressure homogenization (step 4.12).

[0199] Example 8: Bioburden of formulations obtained by high-pressure homogenization alone and without gamma irradiation treatment

[0200] High-pressure homogenization has previously been reported to reduce bioburden, although this effect has been primarily reported at pressures of approximately 100–300 MPa, which is higher than the pressures used in current manufacturing methods (10,000 PSI; 69 MPa). To investigate whether high-pressure homogenization alone, without gamma irradiation, is an effective method for reducing bioburden, the microbial load of the samples was tracked. The samples used for these studies are provided in Tables 12 and 14. Results for these sample types are provided in Tables 13 and 15A and 15B, respectively.

[0201] Table 12: Sample group 1 used for bioburden analysis

[0202]

[0203] Table 13: Microbial load of samples treated by high-pressure homogenization only, and samples collected before and after the high-pressure homogenization step.

[0204]

[0205]

[0206] The outlet hose was removed from the high-pressure homogenizer for the final pass, and the sample was collected directly from the steel outlet. It was also wiped with ethanol before collection.

[0207] The presence of TAMC, TYMC, and E. coli was measured using Eurofins. The detection limits for TAMC and TYMC were validated at 10 cfu / g. Results below this value were reported as <10 cfu / g. This limit is significantly lower than the quality standards of <1000 cfu / g and <100 cfu / g for TAMC and TYMC, respectively.

[0208] Table 13 shows the bioburden results for samples treated with high-pressure homogenization only, as well as samples collected before and after the high-pressure homogenization step. It can be seen that after storage at 40°C for one month, no microbial load was detected in any sample.

[0209] At the 2-month timeframe, homogenized samples of batch 1 (CER22005-F2b) showed detectable levels of aerobic microorganisms, yeast, and mold above quality standards at 25°C, while no microorganisms were detected in the unhomogenized samples. For batch 2 (CER22005-F3a), low levels of aerobic microorganisms and yeast and mold below quality standards were detected in the unhomogenized samples, while no microorganisms were detected in the homogenized samples. For both batches 1 and 2, no microorganisms were detected in either the unhomogenized or homogenized samples at 40°C. For the third batch (batch 3, CER22005-P1b), no microorganisms were detected in any sample at either 25°C or 40°C.

[0210] Table 14: Sample group 2 for biological load analysis

[0211]

[0212] As a control, a portion of this batch was sent for gamma irradiation. After gamma irradiation, this portion was filled into glass vials inside a laminar flow hood (irradiation group). The remainder of the batch was retained and not subjected to gamma irradiation (homogenization group only). Only a portion of the homogenization group was filled inside the laminar flow hood, while the other portion was filled outside the laminar flow hood.

[0213] The presence of TAMC, TYMC, and E. coli was measured using Eurofins. The detection limits for TAMC and TYMC were validated at 10 cfu / g. Results below this value were reported as <10 cfu / g. This limit is significantly lower than the quality standards of <1000 cfu / g and <100 cfu / g for TAMC and TYMC, respectively.

[0214] The bioload results for the second group of formulations are shown in Tables 15A and 15B. The results showed that after 12 weeks of storage at 25°C or 40°C, no microbial load was detected in any sample, regardless of whether the sample was filled inside or outside the laminar flow hood.

[0215] Table 15A: Microbial load of the preparations in group 2

[0216]

[0217] Table 15B: Group 2 data from weeks 8-12

[0218]

[0219] In summary, the fact that none of the prepared samples contained any microbial load above the detection limit, even when filled outside the laminar flow hood, suggests that the manufacturing process itself appears sufficient to maintain the bioload below the detection limit without gamma irradiation. However, one pre-homogenized sample and one post-homogenized sample from Group 1 did show microbial counts after storage at 25°C for 2 months, making it impossible to determine the extent of the bioload reduction effect provided by high-pressure homogenization. Instead, the inconsistent presence of microbial contamination is likely due to contamination of individual vials during filling due to a non-sterile laboratory environment. Overall, the results of Group 2 indicate that formulations without any detectable microbial load can be prepared without gamma irradiation or other bioload reduction steps. Nevertheless, aseptic filling is recommended. Furthermore, it is suggested that the final commercial manufacturing method include ultra-high temperature (UHT) treatment as a bioload reduction step to remove any potential microbial contaminants from the raw materials or during manufacturing steps upstream of high-pressure homogenization and filling.

[0220] Example 9: Using Design of Experiments (DOE) to study small changes in a formulation

[0221] Formulations were screened for variations in pH, buffer strength, flavoring agent type, flavoring agent concentration, and sweetener concentration. The ranges shown in Table 16 below were used for each factor:

[0222] Table 16:

[0223]

[0224] The stability of the formulation was monitored for 3 months at 2-8℃, 25℃, and 40℃. The following observations are clearly evident from the data:

[0225] Appearance: Throughout the 3-month stability study, the appearance of all formulations remained unchanged under all storage conditions and was within the quality standard of "white to off-white emulsion with no phase separation".

[0226] Assay: For all active formulations, the assay was completely within quality standards throughout the entire 3-month storage period under all storage conditions, and there was no evidence of assay decline.

[0227] Related substances determination: For any active formulation tested under any storage conditions, there was no evidence of an increase in total related substances or any increase in any individual impurities.

[0228] pH: During the 3-month stability study of all tested formulations, the pH decreased significantly. This will be discussed in more detail in the following examples.

[0229] Particle size: The particle size of all active and placebo formulations remained stable under all storage conditions.

[0230] Viscosity: Viscosity was acceptable for all formulations, and no significant changes of concern were observed throughout the 3-month study. Viscosity data collected are for informational purposes only.

[0231] Color: Color was acceptable for all formulations, and no significant changes of concern were observed throughout the 3-month study. Color data collected are for informational purposes only.

[0232] Taste: When stored at 25°C or 40°C for 3 months, the taste of all preparations changed, while when stored at 2-8°C, the taste changed little or not at all.

[0233] The overall conclusion is that the liquid emulsions are robust to variations in appearance, assays, related substances, particle size, viscosity, and color from factors that change in the design (pH, buffer strength, flavoring agent type, flavoring agent concentration, and sweetener concentration). Taste is difficult to evaluate because it is highly subjective and difficult to quantify without the participation of a large sensory panel, which is beyond the scope of this formulation study. However, it can be concluded that the type of flavoring agent (vanilla or berry) is not of primary importance to flavoring agent stability during storage, and they exhibit similar behavior during storage.

[0234] Aside from taste, the only other property that was unstable during storage was pH, which decreased during the 3-month stability study. The decrease was greater at higher storage temperatures and depended on the formulation, as some formulations experienced a greater pH decrease than others.

[0235] To evaluate the most significant factors leading to pH decrease, as shown in Figures 5A-5I, the active formulations were graded at 25°C in order of maximum to minimum pH decrease. It was found that changes at 25°C were most useful for comparing the pH stability of the formulations, as room temperature represents the expected storage conditions. By comparing the pH stability grades, the following conclusions can be drawn: Initial pH: The formulation with an initial pH of 6.5 was the most stable, and the formulation with an initial pH of 7.8 was the least stable. However, at 40°C, the formulation with an initial pH of 6.5 began to decrease after 3 months, likely because the pH deviated from the pKa of the most effective buffer, phosphate buffer (pKa 6.8). Based on these results, it was decided to maintain the pH of the formulation at a slightly higher level of 6.8 to optimize pH stability and avoid the decrease observed at 40°C at subsequent time points for formulations with low initial pH.

[0236] Flavoring level: The most stable formulations have low flavoring levels, while the least stable formulations have high flavoring levels.

[0237] Flavoring type: Vanilla and berry flavorings performed similarly and showed no significant difference in pH stability relative to flavoring type.

[0238] Buffer strength: The most stable formulations have high buffer strength, while the least stable formulations have low buffer strength. However, it is fairly certain that both flavoring level and buffer strength are important for pH stability, as previous experiments have shown that flavored formulations are less stable than unflavored formulations, and it seems logical that higher buffer strength would improve pH stability.

[0239] Sucralose level: Sucralose level does not appear to be a major factor in pH stability.

[0240] The overall conclusion is that formulations with higher buffer strength, lower flavoring levels, and an initial pH of 6.8 improved pH stability.

[0241] Example 10: Introducing ultra-high temperature (UHT) treatment as a biological load control step

[0242] The AC-OLE-01-VA batch manufactured at a scale of 85 kg was stable and showed no microbial growth during 12 months of storage at 25°C, even though a specific bioload reduction step was not present in the method. Nevertheless, it is considered necessary to include a bioload reduction step in the final commercial manufacturing method. Gamma irradiation was used on previously manufactured unflavored formulations, but this was found to negatively impact taste and therefore unsuitable for commercial products. Sterilization filtration was attempted, but the formulation was found to clog the sterilization-grade filter. High-pressure heat treatment (HPTP) was also considered, but this method has limitations in terms of obtaining manufacturing-scale equipment.

[0243] Conversely, ultra-high temperature treatment (UHT) was examined and found to be a suitable method, which can also be scaled up to large volumes. The following sections describe the development of a UHT method suitable for inclusion in the manufacturing process.

[0244] A study was designed to investigate the effect of UHT parameters on AC-OLE-01-VA oral liquid emulsion. The active AC-OLE-01-VA formulation, with the composition shown in Table 17 below, was evaluated in a DOE study.

[0245] Table 17: Composition of the AC-OLE-01-VA formulation used in UHT studies

[0246]

[0247] The emulsion preparation process involves three main steps, in the following order:

[0248] a) High-shear mixing

[0249] b) Ultra-high temperature treatment (UHT)

[0250] c) High-pressure homogenization (HPH)

[0251] A 10L batch was prepared for UHT treatment. The initial 7L and final 1L of the UHT treatment batch were discarded, and only the intermediate 2L was collected for high-pressure homogenization. This was to ensure that dilution did not affect the results, as previous studies had shown that the first few liters were diluted. The dilution effect is due to the fact that the UHT was first run with pure water to stabilize the flow rate and temperature, and then the formulation was added after the UHT system had been heated and the parameters had stabilized.

[0252] Five UHT process parameters that can be controlled in the UHT method were identified. One of these factors, throughput, was not included in the initial DOE design but was intended to be evaluated after the final method was determined. The other four process parameters were evaluated in the component factorial DOE, as shown in Table 18 below. Three center points were included to evaluate system repeatability.

[0253] Table 18: Design of Equipment (DOE) for UHT Process Development

[0254]

[0255] Controlled by flow rate and holding tube

[0256] This study focuses primarily on assessing how UHT affects product quality attributes, rather than tracking long-term stability. After preparation, the taste, texture, particle size, viscosity, and related parameters of the samples were tested. Samples were also stored at 25°C, and particle size and texture were tested after two weeks and one month to identify any impact of UHT on stability. Furthermore, this study was not intended to assess the long-term stability of UHT-processed formulations. Subsequent studies using optimized UHT methods were conducted to prepare samples to obtain long-term stability.

[0257] Tables 19 and 20 present the assays and total relevant information as a function of holding time and UHT temperature. Unbound by theory, if UHT treatment led to chemical degradation of the AC-OLE-01-VA formulation, a decrease in assays could be expected, and this would be associated with an increase in UHT runs with higher temperatures and longer holding times. In other words, moving from the top left corner of the table (130°C & 3 s) to the bottom right corner (145°C & 45 s) would be expected to result in lower assays and an increase in total relevant information. However, this was not expected, and there was no indication that higher temperatures and longer holding times led to chemical degradation of glyceryl tricaprylate. There was also no indication that individual impurities increased at higher temperatures and longer holding times. Therefore, it is concluded that the formulation is highly robust to UHT treatment, and the entire range of holding times and temperatures studied in the DOE can be selected without affecting the assays and relevant information of the formulation.

[0258] Table 19: Measurement results of DOE batches for UHT process development.

[0259]

[0260] Table 20: Overall correlation results of DOE batches in UHT process development.

[0261]

[0262] The UHT process for run #3 (batch D22081702, 1802) failed because the UHT pump stopped during operation due to pressure buildup in the UHT system. Therefore, this data is displayed in gray font because it does not represent actual UHT operation with the selected UHT parameters.

[0263] The physical stability and particle size of the emulsion were also evaluated. Comparing the particle size before and at T0, it was clear that the particle size distribution varied significantly before high-pressure homogenization, but the final particle size was very similar after high-pressure homogenization. This means that the particle size was affected by the UHT method, but the high-pressure homogenization step eliminated this difference and resulted in a virtually identical particle size distribution in the final product, independent of the UHT method. It should also be noted that for all batches, the particle size distribution did not actually change after one month of storage at 25°C, except for one batch (run #3) where the UHT pump stopped during the UHT process due to pressure buildup in the system. This resulted in some product remaining in the system for a long time until the pump was restarted, and therefore does not represent a true UHT run and should be ignored. Therefore, it is concluded that, in terms of particle size, the AC-OLE-01-VA is also highly robust to UHT treatment, and the entire holding time and temperature range studied in the DOE can be selected without affecting the particle size distribution or physical stability of the finished product.

[0264] The taste of the UHT-treated batches was also evaluated, and all combinations of UHT temperature and holding time were found to be acceptable.

[0265] Overall, it can be concluded that the formulation is robust to UHT treatment in terms of appearance, chemical stability, physical stability, and taste within a UHT temperature range of 130°C to 145°C and a holding time of 3 to 45 seconds.

[0266] From the manufacturing process, a UHT operation failure was noted because the UHT pump shut down during operation when the system pressure approached the 25 bar cutoff point. This occurred in run #3 at a flow rate of 100 L / hr; the UHT temperature was 130°C, and the cooler temperature was 20°C. It was found that the higher flow rate and lower temperature led to greater pressure buildup, and therefore this situation can be avoided in production batches by controlling these parameters.

[0267] To evaluate the bioburden reduction efficiency of AC-OLE-01-VA liquid emulsion under UHT treatment, a microbial challenge test was performed. AC-OLE-01-VA liquid emulsion (50 mM phosphate buffer, pH 6.8, 0.2% vanilla, 0.05% sucralose) was prepared, and a crude emulsion was prepared by high-shear mixing.

[0268] With E. coli ( E. coli Salmonella ( Salmonella Listeria monocytogenes ( Listeria monocytogenes Staphylococcus aureus Staphylococcus aureus ) and Bacillus cereus ( Bacillus cereus ) and thermophilic strobilurinary spores ( Geobacillus StearothermophilusThe spores were used to microbially challenge the formulation, followed by UHT treatment at 135°C for 2.35 seconds.

[0269] Log reduction was measured by comparing colony-forming units per gram (cfu / g) before and after UHT treatment, and the results are shown in Table 21 below.

[0270] Table 21: Logarithmic decrease of different challenging microorganisms after UHT treatment at 135℃ for 2.35 seconds

[0271]

[0272] Commercial sterility testing: As a further evaluation of the efficiency of UHT treatment, commercial sterility tests were also conducted. Microbial challenges against *Escherichia coli*, *Salmonella*, *Listeria monocytogenes*, *Staphylococcus aureus*, and *Bacillus cereus* were performed by UHT treatment at 135°C for 2.35 seconds, followed by incubation at 30°C for 14 days and at 55°C for 7 days. Microbial growth was then assessed. The results are shown in Table 22 below.

[0273] Table 22: Commercial sterility test results of formulations subjected to microbial challenge and UHT treatment

[0274]

[0275] No microbial growth was observed, demonstrating that UHT at 135°C for 2.35 seconds can yield a commercially sterile formulation after UHT treatment of the studied pathogen.

[0276] Example 11: Stability of formulations prepared using UHT treatment included in the manufacturing process

[0277] Numerous batches were prepared using UHT treatment, which was incorporated into the manufacturing process. These batches were prepared with varying buffer strengths and vanilla flavoring concentrations to optimize long-term stability, as formulation screening DOEs showed that lower flavoring concentrations and higher buffer strengths improved the pH stability of the formulations. The prepared formulations are shown in Table 23, and the compositions are shown in Table 24.

[0278] Table 23: Active formulations with different flavoring agent concentrations and buffer strengths prepared by UHT treatment at 135°C and a holding time of 5 seconds.

[0279]

[0280] Table 24: Composition of the active formulation treated with UHT

[0281]

[0282] The data clearly show that all formulations are stable in terms of appearance, assays, related substances, particle size, and color. The only properties that showed significant changes during storage were pH, which decreased during storage, and taste, which changed slightly when stored at elevated temperatures.

[0283] Figures 6A-6D The pH evolution of the active formulations with different levels of vanilla flavoring and buffer concentrations is shown in the graphs. It is clear from these graphs that the active formulations, relative to pH, can be arranged in order from most stable to least stable as follows:

[0284] 100mM buffer, unflavored > 100mM buffer, 0.1% vanilla > 100mM buffer, 0.2% vanilla > 50mM buffer, 0.2% vanilla

[0285] These results indicate that higher buffer strength (100 mM vs 50 mM) and lower flavoring agent concentrations both lead to more stable formulations. This is consistent with the results of the formulation screening DOE.

[0286] It should be noted that the unflavored formulation only reached the 3-month time point, therefore the data on the unflavored formulation is limited. However, the 3-month data already showed that the pH was more stable than that of the flavored formulation, as the pH of the sample at 40°C remained almost completely unchanged.

[0287] The overall conclusion drawn from batches prepared using UHT treatment during the manufacturing process is that UHT was successfully incorporated into the method, and the batches were prepared at a higher buffer strength of 100 mM instead of 50 mM. Batches with a 100 mM buffer strength showed better long-term stability than batches with a 50 mM buffer strength but otherwise comparable composition. Reducing the flavoring concentration (e.g., from 0.2% to 0.1% vanilla) further improved stability. Therefore, there are options to improve storage stability by adjusting the buffer strength to 100 mM phosphate buffer and / or reducing the vanilla flavoring concentration.

[0288] Based on the successful introduction of UHT processing, the recommended final manufacturing method is as follows: Figure 7 As shown, UHT is included between high-shear mixing and high-pressure homogenization.

[0289] Example 12: Large-scale manufacturing method of unflavored emulsion

[0290] Large-scale batches of unflavored AC-OLE-01 to AC-OLE-10 and vanilla-flavored AC-OLE-01-VA formulations have been manufactured for clinical trials of unflavored and vanilla-flavored emulsions. The manufacturing methods and storage stability of these large-scale batches are briefly outlined. Unflavored liquid emulsions were manufactured on a 20 kg scale. Formulations AC-OLE-06 and AC-OLE-08 containing citrem, as shown in Table 1, also include a pH adjustment step and slightly different excipients, but are otherwise identical. The manufacturing method can utilize an overhead high-shear mixer instead of an inline high-shear mixer. It should be noted that gamma irradiation of the product after filling was used here as a bioburden reduction method.

[0291] Ten unflavored formulations, named AC-OLE-01 to AC-OLE-10, were manufactured for clinical trials. A step-by-step overview of the manufacturing process is provided below. Figure 1 The text shows:

[0292] Step 1: Preparation of NaOH

[0293] 1.1 Transfer the low-heat raw water to a suitable beaker.

[0294] 1.2 Weigh sodium hydroxide into a suitable container.

[0295] 1.3 Transfer the sodium hydroxide to a beaker of low-heat raw water and stir using a top-mounted stirrer equipped with a stainless steel stirrer until all the sodium hydroxide has dissolved.

[0296] Step 2: Preparation of 50mM phosphate buffer at pH 6.8

[0297] 2.1 Weigh sodium dihydrogen phosphate dihydrate into a suitable container.

[0298] 2.2 Weigh the low-heat raw water into a 30L steel tank 1.

[0299] 2.3 Add the sodium dihydrogen phosphate dihydrate weighed in step 2.1 to the low-heat raw water weighed in step 2.2, and stir the mixture using a top-mounted stirrer until all the sodium dihydrogen phosphate dihydrate in stainless steel tank 1 is dissolved.

[0300] 2.4 Adjust the pH of the solution to 6.8 (target value ± 0.1) using the 2M NaOH prepared in step 1.3. Stir the solution for 1 minute after each addition of NaOH solution.

[0301] Step 3: Emulsion Preparation

[0302]

[0303]

[0304] Step 4: Fill

[0305]

[0306] Step 5: Gamma irradiation

[0307]

[0308] exist Figure 8A and Figure 8B The paper provides particle size measurements after high-shear mixing (top) and after five passes of high-pressure homogenization.

[0309] Example 13: Large-scale manufacturing method of flavored emulsion

[0310] Use such as Figure 9 The manufacturing method outlined herein was used to manufacture three active vanilla flavoring batches (AC-OLE-01) in an 85 kg scale. Compared to the method described in Example 12 for the unflavored formulation, the method for manufacturing the vanilla flavoring formulation comprises six key differences:

[0311] 1. Add vanilla flavoring and sucralose to the buffer-emulsifier mixture. Add sucralose directly to the buffer-emulsifier mixture, and add vanilla flavoring by first mixing it with glyceryl triethyl.

[0312] 2. The bottle and cap are subjected to gamma radiation before filling. This is done because there is no gamma radiation after filling.

[0313] 3. Fill the formulation into a 100mL amber glass vial instead of a 30mL vial.

[0314] 4. Fill the bottle in the biocabinet to avoid microbial contamination. This is also because there is no gamma irradiation after filling.

[0315] 5. No gamma radiation was applied after filling because gamma irradiation has a negative impact on taste.

[0316] 6. Only two passes of high-pressure homogenization were performed, as particle size measurements indicated that this was sufficient.

[0317] This shows one of the active formulations after high-shear mixing ( Figure 10A ) and after the second high-pressure homogenization ( Figure 10B Particle size measurement during the process.

[0318] The stability of the emulsion with vanilla flavoring at 2-8°C, 25°C and 60% relative humidity (RH) and at 40°C and 75% RH for 3 months, 6 months, 9 months and 12 months is shown in Table 25.

[0319] Table 25: Characteristics of the manufactured emulsion

[0320]

[0321] Example 14: Alternative Mass Manufacturing Methods

[0322] A new manufacturing method has been developed, which has the same characteristics as... Figure 9 The steps shown are essentially the same, but with some modifications (see [link]). Figure 11 Key differences between the two processes include the use of disodium hydrogen phosphate instead of sodium hydroxide to adjust the pH to 6.8. Sodium dihydrogen phosphate and disodium hydrogen phosphate can be added in the correct ratio to achieve the target pH of 6.8. Other differences include the use of high-shear mixing with recirculation and the use of 7,500 PSI instead of 10,000 PSI during high-pressure homogenization.

[0323] Example 15: Summary and Conclusion

[0324] The provided formulation exhibits very good stability, even at room temperature; however, the pH decreases over time. To further improve stability, it was decided to investigate the factors affecting pH stability, and it was determined that lower flavoring agent concentrations and higher buffer strength significantly improved pH stability.

[0325] To improve long-term stability at room temperature, it is recommended to increase the buffer strength to 100 mM and reduce the vanilla flavoring concentration to 0.1%. This provides the composition shown in Table 23, and the formulation is referred to as AC-OLE-01-VA-b.

[0326] Table 23: Active Vanilla Flavoring Preparations, AC-OLE-01-VA-b

[0327]

[0328] Although microbially stable formulations can be prepared without any bioload reduction steps, it is considered necessary to include a bioload reduction step in the final commercial manufacturing process.

[0329] A UHT method was developed, and the AC-OLE-01-VA formulation was shown to be highly robust to UHT treatment, with no significant differences in physical and chemical properties or taste between low (130°C) and high (145°C) UHT treatment temperatures or short (3 seconds) and long (45 seconds) holding times. In other words, the formulation can withstand a wide range of UHT method conditions without affecting product quality.

Claims

1. An emulsion, which comprises: Approximately 20%-60% by weight of tricaprylic acid glycerides; Approximately 0.1-10% by weight of emulsifier; Approximately 0.1-10% by weight of glycerin; and Approximately 10 mM - 200 mM phosphate buffer (pH 6.0-8.0).

2. The emulsion according to claim 1, wherein the emulsifier comprises phospholipids, polyethylene glycol glycerol hydroxystearate, glycerol monoester and glycerol diester citrate, or any combination thereof.

3. The emulsion according to claim 1 or claim 2, wherein the emulsifier is Phospholion 90G, Kolliphor® RH40, or a combination thereof.

4. The emulsion according to any one of claims 1-3, wherein the emulsion comprises: 50% by weight of tricaprylic acid glyceride; 4% by weight Phospholipon® 90g; 2% by weight of Kolliphor RH40; 2.5% by weight of glycerin; and 20 mM - 150 mM phosphate buffer (pH 6.8).

5. The emulsion according to any one of claims 1-4, wherein the emulsion further comprises a sweetener.

6. The emulsion according to claim 4, wherein the sweetener comprises acesulfame potassium, advans, aspartame, saccharin, sucralose, monk fruit, purified stevia leaf extract, or any combination thereof.

7. The emulsion according to any one of claims 5 or 6, wherein the emulsion comprises about 0.01% by weight to about 1% by weight of a sweetener.

8. The emulsion according to claim 7, wherein the sweetener is sucralose and is present at a concentration of about 0.05% by weight.

9. The emulsion according to any one of claims 1-8, wherein the emulsion further comprises a flavoring agent.

10. The emulsion according to claim 9, wherein the flavoring agent is oil-soluble.

11. The emulsion according to any one of claims 9 or 10, wherein the flavoring agent is vanilla, mango, berry, or any combination thereof.

12. The emulsion of claim 11, wherein the emulsion comprises about 0.1% to about 0.3% by weight of vanilla flavoring.

13. The emulsion of claim 12, wherein the vanilla is present at a concentration of about 0.1% by weight or about 0.2% by weight.

14. The emulsion according to any one of claims 1-13, wherein the phosphate buffer is a 100 mM phosphate buffer and the flavoring agent is vanilla present at a concentration of about 0.1% by weight.

15. The emulsion according to any one of claims 1-13, wherein the phosphate buffer is a 50 mM phosphate buffer and the flavoring agent is vanilla present at a concentration of about 0.2% by weight.

16. An emulsion, comprising: Medium-chain triglycerides (MCTs); One or more emulsifiers; Buffer solution; and Sweeteners and / or flavoring agents; The emulsion mentioned above is an emulsion intended for oral administration.

17. The emulsion according to claim 16, wherein the MCT is glyceryl trioctanoate.

18. The emulsion of claim 16, wherein the emulsion further comprises a triol.

19. The emulsion of claim 16, wherein the one or more emulsifiers comprise phospholipids, polyethylene glycol glycerol hydroxystearate, glycerol monoester and citrate of diglycerides, or combinations thereof.

20. The emulsion of claim 18, wherein the triol comprises glycerol.

21. The emulsion according to claim 16, wherein the sweetener comprises acesulfame potassium, advans, aspartame, saccharin, sucralose, monk fruit, purified stevia leaf extract, or a combination thereof.

22. The emulsion according to claim 21, wherein the sweetener is sucralose, stevia, or any combination thereof.

23. The emulsion according to any one of claims 21 or 22, wherein the emulsion comprises about 0.01% by weight to about 1% by weight of a sweetener.

24. The emulsion of claim 23, wherein the sweetener is sucralose and is present at a concentration of about 0.05% by weight.

25. The emulsion of claim 16, wherein the flavoring agent is oil-based.

26. The emulsion of claim 25, wherein the flavoring agent comprises vanilla, mango, berries, or a combination thereof.

27. The emulsion according to any one of claims 25 or 26, wherein the flavoring agent is present in an amount of about 0.05% by weight to about 0.5% by weight.

28. The emulsion according to any one of claims 25-27, wherein the flavoring agent comprises vanilla.

29. The emulsion of claim 28, wherein the vanilla is present at a concentration of about 0.1% by weight or about 0.2% by weight.

30. The emulsion according to any one of claims 25-27, wherein the flavoring agent comprises berries.

31. The emulsion of claim 30, wherein the flavoring agent is present at a concentration of about 0.3% by weight.

32. The emulsion according to any one of the preceding claims, wherein the emulsion is stable at about 2°C to about 8°C for a period of at least about 3 months, 6 months, 9 months, 12 months or longer.

33. The emulsion according to any one of the preceding claims, wherein the emulsion is stable at about 25°C for a period of 3 months, 6 months, 9 months, 12 months or longer.

34. The emulsion according to any one of the preceding claims, wherein the emulsion is stable at about 40°C for a period of 3 months, 6 months, 9 months, 12 months or longer.

35. A method for preparing an emulsion containing glyceryl tricaprylate, wherein the method comprises: a) Feed the ingredients, which contain buffer, glyceryl trioctanoate and one or more emulsifiers, into the container; b) The buffer solution, glyceryl trioctanoate, and one or more emulsifiers are mixed under high shear in the container to form a crude emulsion; c) Optionally, the crude emulsion is sterilized to form a sterile emulsion; and d) The sterile emulsion is homogenized under high pressure (HPH) to form an emulsion containing tricaprylic acid glycerides.

36. The method of claim 35, wherein step (c) is an ultrathermal treatment (UHT) step, an irradiation step, or a combination thereof.

37. The method according to claim 35 or claim 36, wherein step (c) is a UHT step.

38. The method of claim 37, wherein the UHT step (step c) is performed at a temperature of about 130°C to about 145°C for about 3 seconds to about 45 seconds.

39. The method of claim 38, wherein the temperature is about 135°C and the holding time is about 2-3 seconds.

40. The method according to any one of claims 35-39, wherein step (c) does not include the irradiation step.

41. The method of claim 35, wherein the flavoring agent is mixed with the tricaprylic acid glyceride in step (a).

42. The method according to any one of claims 35-41, wherein the one or more emulsifiers comprise Phospholipon® 90G, Kolliphor® RH40, or a combination thereof.

43. The method according to any one of claims 35-42, wherein gamma irradiation is not used.

44. The method according to any one of claims 35-43, wherein the emulsion is the emulsion according to any one of claims 1-34.

45. The method according to any one of claims 35-44, wherein the emulsion is stable for at least 3 months, at least 6 months, or at least 12 months.

46. ​​The method according to any one of claims 35-45, wherein the emulsion has a particle size of 0.01-10 µm.

47. The method according to any one of claims 35-45, wherein the high-pressure homogenization is performed at a pressure of about 5,000 PSI to about 10,000 PSI.

48. The method of claim 47, wherein the high-pressure homogenization is performed at a pressure of about 7,500 PSI.

49. The method according to any one of claims 35-48, wherein the method further comprises a high-shear mixing step with recirculation.

50. A method for treating a disease or disorder in a subject in need, the method comprising administering to the subject an effective amount of the emulsion according to any one of claims 1-34.

51. A method of treating a disease or disorder in a subject in need, the method comprising administering an effective amount of an emulsion to the subject, the emulsion comprising: Approximately 20%-60% by weight of tricaprylic acid glycerides; Approximately 0.1-10% by weight of emulsifier; Approximately 0.1-10% by weight of glycerin; and Approximately 10 mM - 200 mM phosphate buffer (pH 6.0-8.0).

52. The method of claim 51, wherein the emulsion comprises: 50% by weight of tricaprylic acid glyceride; 4% by weight Phospholipon® 90g; 2% by weight of Kolliphor® RH40; 2.5% by weight of glycerin; and 20 mM - 150 mM phosphate buffer (pH 6.8).

53. The method according to any one of claims 47-49, wherein the disease or disorder includes age-related memory disorder (AAMI), Alzheimer's disease (AD), Parkinson's disease, Friedreich ataxia (FRDA), GLUT1 deficiency epilepsy, dwarfism syndrome, Rabson-Mendenhall syndrome, coronary artery bypass graft (CABG) dementia, anesthesia-induced memory loss, Huntington's disease, infantile spasms, migraine, and related headaches.

Images