Composition and method for producing ultra-high purity tricaprylin

Abstract

The disclosure of this invention provides ultra-high purity tricaprylin and methods for producing compositions comprising ultra-high purity tricaprylin. The disclosure also provides methods for using these compositions for the treatment of diseases.

Description

Technical Field

[0001] Cross - reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 472,229, filed on June 9, 2023, and No. 63 / 607,779, filed on December 8, 2023, the disclosures of which are hereby incorporated by reference in their entireties.

[0002]

[0002] The present invention generally relates to compositions and methods of making ultra - high purity tricaprilin.

Background Art

[0003]

[0003] Tricaprilin (synonymously, tricaprylin, trioctanoyl glycerol, tricaprylyl glycerol, glycerol trioctanoin, tricapryloyl glycerol, octanoic acid - 1,2,3 - propanetriyl ester, glycerol tricaprylate, tricaprylyl glycerol, glycerol tricaprylate, trioctanoic acid glycerol, tricaprylyl glyceryl, caprylic acid triglyceride, tricaprilin, tricaprylyl glycerol, etc.) is a triglyceride of caprylic acid and is usually produced by the esterification of caprylic acid and glycerol.

[0004]

[0004] Tricaprylin is used in pharmaceutical preparations, for example, as a neutral carrier or excipient of the active ingredient, as an absorption enhancer, and as a solubilizer. It is also used in the preparation of water-in-oil-in-water multiple emulsions for incorporating water-soluble drugs, and as an oily phase for obtaining stable microcapsules. Because it is readily miscible with natural oils and surfactants, tricaprylin is used as a fatty component in two-phase foam bath products, as well as in products such as a fixative for sunscreen creams, oils, fragrances, and air fresheners. High doses of tricaprylin have also been used as an active ingredient in pharmaceutical compositions for Alzheimer's disease.

[0005]

[0005] However, conventional methods for producing fatty acid polyol esters, particularly fatty acid glycerol esters, such as medium-chain triglycerides (MCTs), and especially tricaprylin, result in relatively high levels of impurities and by-products. These impurities are known to be toxic, particularly toxic halide by-products and impurities. In particular, the presence of these impurities and toxic by-products makes them unsuitable for use in high doses. Therefore, there is an unmet need for a method for producing ultra-high purity tricaprylin that may be widely applicable to all MCTs. [Overview of the Initiative] [Means for solving the problem]

[0006]

[0006] In some embodiments, the Disclosure comprises ultra-high purity compositions comprising at least about 99.2% by weight of tricaprylin and about 0.8% by weight or less of impurities, wherein the tricaprylin is tricaprylin triester; and the impurities comprise one or more of 2-monochloropropanediol, 2-monochloropropanediol monoester, 2-monochloropropanediol diester, 3-monochloropropanediol, 3-monochloropropanediol monoester, 3-monochloropropanediol diester, or any combination thereof. In some embodiments, the ultra-high purity composition comprises at least about 99.5% by weight of tricaprylin and about 0.5% by weight or less of impurities. In some embodiments, the ultra-high purity composition comprises at least about 99.7% by weight of tricaprylin and about 0.3% by weight or less of impurities. In some embodiments, the ultra-high purity composition may contain 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester at concentrations of 35 ppb or less. In some embodiments, the ultra-high purity composition may contain 3-monochloropropanediol and 3-monochloropropanediol diester, respectively, at concentrations of less than 35 ppb. In some embodiments, the impurities may further include glycidol, the monoester tricaprylin, the diester tricaprylin, or the tetraester tricaprylin. In some embodiments, the impurities may further include unreacted reactants.

[0007]

[0007] In one embodiment, the Disclosure also relates to a method for producing an ultra-high purity composition of tricaprylin, comprising: (a) supplying caprylic acid, concentrated acid, glycerol, and water into a first reactor; (b) reacting the caprylic acid, concentrated acid, glycerol, and water in the first reactor to form a product mixture containing tricaprylin and impurities, wherein the impurities contain unreacted reactants and optionally undesirable by-products; and (c) adding an aqueous solution of an organic solvent and a basic salt to a second reactor to form a two-phase system comprising an upper organic phase and a lower aqueous phase. The method includes the steps of: (d) forming a phase mixture; (b) adding a product mixture from the fractionated step (b) to the two-phase mixture in step (c) to remove unreacted reactants, wherein the unreacted reactants are present in the aqueous phase; (e) removing the lower aqueous phase from the second reactor; (f) treating the upper organic phase with activated carbon; (g) distilling off the organic solvent, leaving tricaprylin and impurities in the second reactor; and (h) recrystallizing the tricaprylin and impurities to remove the impurities and form ultra-high purity tricaprylin. In some embodiments, step (a) may further include the steps of: (ai) co-feeding caprylic acid and concentrated acid into the first reactor to form a mixture; (aii) heating the mixture to a first temperature under an inert atmosphere; and (aiii) adding glycerol and water to the mixture over a first specified time. In some embodiments, step (b) may further include (bi) stirring the product mixture at a second temperature for a second specified time; (bii) removing the first in-process sample from the first reactor; (biii) checking the first in-process sample for conversion, which is the reaction of a hydroxyl group in glycerol to an ester group in tricaprylin; and (biv) repeating steps (bii) through (biii) until conversion occurs.In some embodiments, step (g) may further include (gi) removing a second in-process sample from a second reactor; (gii) measuring the amount of organic solvent remaining in the tricaprylin and impurities; and (giii) repeating steps (gi) through (gii) until the amount of organic solvent remaining is 500 ppm or less. In some embodiments, step (h) may include (hi) adding a polar solvent to the tricaprylin and impurities to form a second mixture comprising the polar solvent, tricaprylin, and impurities; (hii) cooling the second mixture to a third temperature; (hiii) adding a seed crystal to the second mixture to form a third mixture comprising the seed crystal and the second mixture; (hiv) stirring the third mixture at a third temperature for a third specified time; (hv) cooling the third mixture to a fourth temperature for a fourth specified time; (hvi) cooling the third mixture to a fourth temperature The process may further include: (hvii) maintaining the temperature for a fifth specified time; (hviii) adding water to the third mixture; (hviii) maintaining the third mixture at a fourth temperature; (hix) filtering the third mixture on a filter cooled to a fourth temperature; (hx) washing the third mixture with an aqueous solution of a polar solvent at a fifth temperature; (hxi) repeating the washing step (hx); (hxii) collecting the tricaprylin crystals; and (hxiii) evaporating the residual solvent from the crystals using a rotary evaporator. In some embodiments, the concentrated acid includes sulfuric acid. In some embodiments of the method disclosed herein, the first temperature is in the range of about 90°C to about 120°C. In some embodiments, the first specified time is in the range of about 3 hours to about 5 hours. In some embodiments, the second temperature is in the range of about 90°C to about 120°C. In some embodiments, the second specified time is in the range of about 15 hours to about 24 hours.

[0008]

[0008] In some embodiments, the disclosure also includes pharmaceutical compositions comprising ultra-high purity compositions provided herein. Also disclosed herein are methods for providing preventive or therapeutic treatment for a disease or disorder in a subject in need thereof, comprising the step of administering a composition comprising ultra-high purity tricaprylin to the subject. Non-limiting examples of diseases or disorders include cranial trauma, stroke, hypoxia, myocardial infarction, refeeding syndrome, anorexia, epilepsy, neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, lipid metabolism disorders such as glucose transporter deficiency (GLUT1 deficiency), VL-FAOD, and mitochondrial diseases such as mitochondrial thiolase deficiency, Huntington's disease, cancer such as T-cell lymphoma, astrocytoma, and glioblastoma, HIV, rheumatic diseases such as rheumatoid arthritis, and gout, chronic inflammatory bowel disease, ulcerative colitis, Crohn's disease, lyosomal storage disease, sphingolipidosis, Niemann-Pick disease in particular, diabetes mellitus, migraines and migraine headaches, epilepsy, particularly infantile spasms, and the effects or side effects of chemotherapy. In one embodiment, an ultra-high-purity composition of tricaprylin is administered orally. [Brief explanation of the drawing]

[0009] [Figure 1]

[0009] This figure shows a schematic of the reaction that leads to the formation of monoclopropanediol esters during the production of tricaprylin. [Figure 2]

[0010] This figure shows a schematic of the reaction scheme for the production of tricaprylin. [Figure 3]

[0011] This figure shows a general process for producing an ultra-high purity tricaprylin composition according to a typical embodiment of the present invention. [Figure 4]

[0012] This figure shows a general process for producing an ultra-high purity tricaprylin composition according to a typical embodiment of the present invention. [Figure 5]

[0013] This diagram shows a schematic representation of the production of tricaprylin (TARI-01). [Figure 6]

[0014] This diagram shows the technical setup for a laboratory-scale experiment. The reactor is equipped with (from left to right) an N2 inlet, a mechanical stirrer (stirred), a thermocouple, and a Dean-Stark receiver. [Figure 7]

[0015] This diagram shows a laboratory-scale apparatus for recrystallizing tricaprylin. [Figure 8A]

[0016] This figure shows the CG-MS assay for glycidol in Exp23 AA8219-3. [Figure 8B]

[0017] This figure shows the CG-MS assays for 3-monochloropropanediol (3-MCPD) and 2-monochloropropanediol (2-MCPD) of Exp23 AA8219-3. [Figure 8C]

[0018] This figure shows the CG-MS assay for glycidol in Exp23 AA5433-1. [Figure 8D]

[0019] This figure shows the CG-MS assays for 3-MCPD and 2-MCPD of Exp23 AA5433-1. [Figure 9]

[0020] This figure shows a manufacturing flowchart of the process for producing an ultra-high purity tricaprylin composition according to a typical embodiment of the present invention. [Modes for carrying out the invention]

[0010]

[0021] The following description of embodiments of the present invention is not intended to limit the invention to these embodiments, but rather to enable those skilled in the art to construct and use the invention.

[0011]

[0022] In some embodiments, the present disclosure is based on extensive experimental methods for developing a method for producing ultra-high-purity tricaprylin. These experiments yielded several unexpected results and insights, leading to the development of a novel method for producing tricaprylin with minimal impurities.

[0012]

[0023] Conventional production methods for fatty acid polyol esters, particularly fatty acid glycerol esters, such as medium-chain triglycerides (MCTs), and especially tricaprylin, which involve subsequent multi-stage purification (multiple or more stages of distillation at increasing temperatures), result in relatively high levels of impurities and by-products, particularly due to the high process temperatures required and the starting materials and reagents used, especially halogen-containing substances (e.g., those derived from hydrochloric acid (HCl) or metal catalysts used in the esterification process). In particular, when triglycerides with low acid and hydroxyl values ​​and high degrees of esterification are required, the necessary extreme esterification conditions, especially high temperatures above 180°C and up to 230°C, the required subsequent multi-stage purification (multiple or more stages of distillation at increasing temperatures), and the use of metal catalysts lead to the formation of high levels of toxic by-products and impurities, particularly toxic halide by-products and impurities.

[0013]

[0024] Above all, conventional production methods for fatty acid polyol esters, particularly fatty acid glycerol esters, which involve subsequent multi-stage purification processes (multiple stages of distillation at elevated temperatures), typically produce relatively high levels of impurities and by-products, especially toxic impurities and by-products, such as genotoxic fatty acid glycidyl esters (synonymous with fatty acid glycidyl esters or simply fatty acid GE or GE), and nephrotoxic monochloropropanediol fatty acid esters (synonymous with MCPD fatty acid esters or simply MCPD esters), in particular fatty acid esters of 3-monochloropropanediol (3-MCPD fatty acid ester or 3-MCPD ester) and fatty acid esters of 2-monochloropropanediol (2-MCPD fatty acid ester or 2-MCPD ester).

[0014]

[0025] The exemplary reaction scheme of FIG. 1 illustrates (selected as a non-limiting example) the formation of three of the aforementioned toxic by-products, namely 3-MCPD fatty acid esters, 2-MCPD fatty acid esters, and glycidyl fatty acid esters, which formation occurs when high temperature (e.g., a temperature of 200° C or higher) is applied to a fatty acid triglyceride (e.g., tricaprylin) in the presence of chlorine-containing substances derived from the production process. The substance 3-chloro-1,2-propanediol is formed when glycerol reacts to 3-MCPD in the presence of each of the chlorine-containing substances or chlorides (see FIG. 1).

[0015]

[0026] Moreover, with regard to pharmaceutical and nutritional uses, it is critical and essential, in particular, to control the impurity profile for known toxic by-products, such as the three aforementioned toxic by-products, namely 3-MCPD fatty acid esters, 2-MCPD fatty acid esters, and glycidyl fatty acid esters.

[0016]

[0027] It has been well known for decades that undesirable toxic by-products are formed due to the harsh process conditions that occur during the implementation of conventional esterification / condensation methods for fats and oils. However, attempts have not been made to avoid such harsh conditions by improving or modifying the production process. Mild esterification conditions using bio-based catalysts and lower esterification temperatures reduce the formation of toxic by-products, such as the three aforementioned toxic by-products (i.e., 3-MCPD fatty acid esters, 2-MCPD fatty acid esters, and glycidyl fatty acid esters), but at the same time, they only result in triglycerides having undesirable high acid values and hydroxyl values, and relatively low triglyceride contents with low conversion rates and yields.

[0017]

[0028] As a result, rather than striving to avoid the formation of undesirable toxic byproducts, costly and burdensome pretreatment and / or posttreatment methods are preferred to remove these undesirable harmful byproducts from the desired final product obtained under harsh esterification conditions (i.e., particularly high temperatures above 180°C and up to 230°C, and the use of metal catalysts). Such burdensome posttreatment methods include, among others, the addition of strongly alkaline reagents such as KOH, multi-stage distillation cascades, and heat treatment in strongly alkaline aqueous solutions (as described, for example, in WO2019 / 038320A1 and WO2014 / 012548A1, which are each incorporated herein by reference in their entirety). These posttreatment methods affect and degrade the product quality itself, as well as the overall yield and efficiency. For example, WO2021 / 070209A1 (which is incorporated herein by reference in its entirety) discloses a complex multi-stage extraction process for purifying triglycerides, which uses a saline / organic solvent two-phase extraction system and also uses a chlorinated organic solvent.

[0018]

[0029] However, these post-processing methods often fail to remove the final trace amounts of these undesirable toxic by-products, which then remain in the final product. This is particularly dangerous when high doses of fatty acid polyol esters, especially fatty acid glycerol esters such as tricaprylin (MCTs), are applied to pharmaceutical and nutritional uses (particularly in parenteral applications), leading to the undesirable accumulation of such trace amounts of undesirable toxic by-products in the human body, thus exceeding the legally regulated threshold levels for undesirable toxic by-products. Furthermore, such costly and burdensome post-processing methods, which are solely aimed at subsequent or retrospective removal of undesirable toxic by-products, are also inefficient. This is because these post-processing methods often result in undesirable entrainments of the product and do not increase or affect product quality or purity, such as the degree of esterification or residual content of other impurities (e.g., total halogen content or total acid content).

[0019]

[0030] It would be desirable to devise an efficient production process for directly generating high-quality fatty acid polyol esters, particularly fatty acid glycerol esters, such as MCT (e.g., tricaprylin), which not only possess high purity or minimal levels of by-products and impurities, but also exhibit high esterification and good stability, especially storage stability, and high active ingredient content, without requiring additional costly and burdensome post-processing operations. Consequently, while efforts to find an efficient production process were not lacking in the prior art, they failed to improve the efficiency and performance of existing processes. And even now, an efficient production process has not been devised in the prior art. Furthermore, obtaining such high-quality fatty acid polyol esters, particularly fatty acid glycerol esters, such as MCT (e.g., tricaprylin), is either impossible or not easily possible in the prior art.

[0020]

[0031] Therefore, the fundamental problem of the present invention is to provide an efficient process for producing fatty acid triglycerides (i.e., fatty acid glycerol triesters), particularly tricaprylin, in high purity, in which the disadvantages and / or drawbacks of the prior art described above must be avoided at least partially, or even at least essentially overcome.

[0021]

[0032] Such a production process must, in particular, make each fatty acid polyol ester, especially fatty acid glycerol ester, such as MCT (particularly tricaprylin), available in an efficient manner, with improved quality, and without significant amounts of toxic by-products or impurities. The production process must be feasible at an industrial level, especially on a large scale, and must not involve the excessive and costly post-processing assumed in prior art processes.

[0022]

[0033] Accordingly, the disclosure herein provides ultra-high purity compositions comprising at least about 99.2% by weight of tricaprylin and about 0.8% by weight or less of impurities, and methods for preparing ultra-high purity compositions comprising at least about 99.2% by weight of tricaprylin and about 0.8% by weight or less of impurities. In some embodiments, the disclosure herein provides ultra-high purity compositions comprising at least about 99.5% by weight of tricaprylin and about 0.5% by weight or less of impurities, and methods for preparing ultra-high purity compositions comprising at least about 99.5% by weight of tricaprylin and about 0.5% by weight or less of impurities.

[0023] definition

[0034] The terms “a,” “an,” and “the,” as well as similar demonstrative terms, when used herein, refer to both the singular and plural forms unless otherwise indicated herein or unless clearly inconsistent with the context.

[0024]

[0035] As used herein, the term "approximately" refers to a value or range of values ​​that is one-tenth greater or less than the stated value, but no value or range of values ​​is intended to be limited solely to this broader definition. For example, a value of "approximately 30%" means a value between 27% and 33%. Each value or range of values ​​preceded by the term "approximately" is also intended to encompass aspects of the stated absolute value or range of values.

[0025]

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as they would ordinarily be understood by those skilled in the art. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. If there are multiple definitions of a term herein, the definition in this section shall prevail unless otherwise noted.

[0026]

[0037] Throughout this specification, unless otherwise specified by context, the words “comprise” and “include,” as well as their variations (e.g., “comprises,” “comprising,” “includes,” “including”), are intended to include the described component, feature, element, or process, or group of components, features, elements, or processes, but not to exclude any other complete entity or process, or group of complete entities or processes.

[0027]

[0038] As used herein, "and / or" refers to and encompasses not only all possible combinations of one or more of the related enumerated items, but also the absence of any combination, as interpreted by the alternative ("or").

[0028]

[0039] Furthermore, the disclosure of the present invention is intended to show that any feature or combination of features described herein may be excluded or omitted in some embodiments. For example, if this specification describes a complex comprising components A, B, and C, it is specifically intended that any one of A, B, or C, or any combination thereof, may be omitted and waived individually or in any combination.

[0029]

[0040] The enumeration of value ranges in this Specified Publication is intended only as a simplified way of referring individually to each individual value within that range, unless otherwise indicated herein, and each individual value is incorporated herein as if it were individually enumerated herein. For example, if the concentration range is described as 1% to 50%, then values ​​such as 2% to 40%, 10% to 30%, or 1% to 3% are intended to be explicitly enumerated herein. These are merely examples of what is specifically intended, and all possible combinations of numbers between them, including the minimum and maximum values ​​enumerated, shall be deemed to be expressly described herein.

[0030]

[0041] "Pharmaceutical composition" means a mixture of substances suitable for administration to an individual, including a pharmaceutical agent. As used herein, a pharmaceutical composition comprises one or more compounds as disclosed herein, combined with a suitable pharmaceutical excipient.

[0031]

[0042] As used herein, the terms “patient” and “subject” include “subject” and refer to any organism to which one or more of the compounds described herein are administered by the disclosure of the present invention, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals, e.g., mice, rats, rabbits, non-human primates, humans, insects, worms, etc.). In some embodiments, the subject is human. In some embodiments, the subject may have tumors and / or cancers as disclosed herein. In some embodiments, the cancer is leukemia. In some embodiments, the cancer is colorectal cancer.

[0032]

[0043] Where used herein, the term “effective dose” is defined as the amount of a molecule of the disclosure of the present invention that is necessary to produce a desired physiological change in the cells or tissues to which it is administered. Where used herein, the term “therapeutic effective dose” is defined as the amount of a molecule or composition of the disclosure of the present invention that achieves a desired effect with respect to cancer. In this context, “desired effect” is synonymous with “antitum activity” or “anticancer activity.” Those skilled in the art will readily understand that, in many cases, a molecule may not produce a cure, but may produce a partial benefit, such as the alleviation or improvement of at least one symptom or parameter. In some embodiments, any physiological change that produces some benefit is also considered therapeutically beneficial. Thus, in some embodiments, the amount of a molecule that produces a physiological change is considered an “effective dose” or “therapeutic effective dose.”

[0033]

[0044] The term “ultra-high purity,” as used herein, refers to tricaprylin containing at least about 99.2% by weight of tricaprylin. Ultra-high purity active pharmaceutical ingredients (APIs) contain the highest purity and lowest levels of related substances, including the lowest levels of genotoxic impurities, compared to any currently available MCT oil and other tricaprylin sources. In some embodiments, the tricaprylin contains less than 0.8% by weight of impurities. The term “impurities,” as used herein, refers to undesirable compounds and elements, e.g., unreacted reactants and undesirable by-products and / or by-products, unless otherwise specified herein. In some cases, impurities may have adverse and / or harmful effects on a subject, particularly when the subject is exposed to an amount of impurities exceeding an approved threshold level, either once or over time. In some embodiments, the ultra-high purity tricaprylin disclosed herein is suitable for administration to a subject at a high dose of at least about 20 mg / day. In one embodiment, ultra-high purity tricapriline is suitable for administration to subjects at a high dose of at least approximately 30 mg / day. In another embodiment, ultra-high purity tricapriline is suitable for administration to subjects at a high dose of at least approximately 40 mg / day. The daily amount may be divided into multiple doses or administered as a single dose.

[0034] I. Composition

[0045] In some embodiments, the disclosure includes ultra-high purity compositions comprising at least about 99.2% by weight of tricaprylin and about 0.8% by weight or less of impurities, wherein the tricaprylin is tricaprylin triester. In some embodiments, the ultra-high purity compositions of the disclosure of the present invention may comprise at least about 99.3% by weight of tricaprylin and about 0.7% by weight or less of impurities. In some embodiments, the ultra-high purity compositions may comprise at least about 99.4% by weight of tricaprylin and about 0.6% by weight or less of impurities. In some embodiments, the ultra-high purity compositions of the disclosure of the present invention may comprise at least about 99.5% by weight of tricaprylin and about 0.5% by weight or less of impurities. In some embodiments, the ultra-high purity compositions may comprise at least about 99.6% by weight of tricaprylin and about 0.4% by weight or less of impurities. In some embodiments, the ultra-high purity compositions may comprise at least about 99.7% by weight of tricaprylin and about 0.3% by weight or less of impurities. In some embodiments, the ultra-high purity composition may contain at least about 99.8% by weight of tricaprylin and about 0.2% by weight or less of impurities. In some embodiments, the ultra-high purity composition may contain at least about 99.9% by weight of tricaprylin and about 0.1% by weight or less of impurities. In some embodiments, the ultra-high purity composition may contain at least about 99.99% by weight of tricaprylin and about 0.01% by weight or less of impurities.

[0035]

[0046] In some embodiments, the impurities may include one or more of 2-monochloropropanediol, 2-monochloropropanediol monoester, 2-monochloropropanediol diester, 3-monochloropropanediol, 3-monochloropropanediol monoester, 3-monochloropropanediol diester, or any combination thereof. In some embodiments, the impurities may include unreacted reactants and optionally undesirable by-products. In some embodiments, the impurities may include 2-monochloropropanediol, 2-monochloropropanediol monoester, 2-monochloropropanediol diester, 3-monochloropropanediol, 3-monochloropropanediol monoester, 3-monochloropropanediol diester, unreacted reactants and optionally undesirable by-products, or any combination thereof.

[0036]

[0047] In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 50 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 45 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 40 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 35 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 30 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 25 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 20 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 15 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 14 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 13 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 12 ppb or less.In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 11 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 10 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 9 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 8 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 7 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 6 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 5 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 4 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 3 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 2 ppb or less. In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 1 ppb or less.

[0037]

[0048] In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 35 ppb or less.

[0038]

[0049] In some embodiments, 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester may be present at concentrations of 15 ppb or less.

[0039]

[0050] In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 50 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 45 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 40 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 35 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 30 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 25 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 15 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 14 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 13 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 12 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 11 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 10 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at concentrations of 9 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at concentrations of 8 ppb or less.In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 7 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 6 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 5 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 4 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 3 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at a concentration of 2 ppb or less. In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at concentrations of 1 ppb or less.

[0040]

[0051] In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at concentrations of 35 ppb or less.

[0052] In some embodiments, each of 3-monochloropropanediol and 3-monochloropropanediol diester may be present at concentrations of 15 ppb or less.

[0041]

[0053] In some embodiments, the impurities may include glycidol, tricaprylin monoester, tricaprylin diester, or tricaprylin tetraester. In some embodiments, the impurities may include glycidol, tricaprylin monoester, tricaprylin diester, or tricaprylin tetraester. In some embodiments, the glycidol impurity may be present at 50 ppb or less. In some embodiments, the glycidol impurity may be present at 40 ppb or less. In some embodiments, the glycidol impurity may be present at 35 ppb or less. In some embodiments, the glycidol impurity may be present at 30 ppb or less. In some embodiments, the glycidol impurity may be present at 20 ppb or less.

[0042]

[0054] In some embodiments, ultra-high-purity tricaprylin meets the limits shown in Table 1 below.

[0043] [Table 1-1]

[0044] [Table 1-2]

[0045]

[0055] In some embodiments, impurities can be measured by appropriate analytical techniques. Appropriate analytical techniques include, but are not limited to, gas chromatography, mass spectrometry, or chemical analysis.

[0046]

[0056] In some embodiments, ultra-high purity compositions of tricaprylin can be further characterized by measuring one or a combination of the following: acid value, saponification value, refractive index, water content, total number of aerobic microorganisms, total number of yeasts and molds, and elemental impurities by ICP-MS.

[0047] II. Method for preparing ultra-high purity compositions

[0057] The disclosure of the present invention further encompasses a method for preparing an ultra-high purity composition of tricaprylin as disclosed herein. The general reaction is an esterification reaction, in which an acid can be reacted with an alcohol to result in the formation of an ester.

[0048]

[0058] This method generally includes the steps of reacting an alkylcarboxylic acid with an alkyltriol at a specified temperature to form a product mixture, and purifying the product mixture to obtain an ultra-high purity composition of tricaprylin. The product mixture contains tricaprylin and impurities. The purification step includes separating the tricaprylin and impurities in an organic solvent, distilling the organic solvent, and recrystallizing the product mixture to obtain an ultra-high purity composition of tricaprylin.

[0049]

[0059] Figure 2 shows a general reaction according to the disclosure of the present invention. The reaction step includes (a) supplying caprylic acid, concentrated acid, glycerol, and water into a first vessel, and (b) reacting the caprylic acid, concentrated acid, glycerol, and water in the first vessel to form a product mixture containing tricaprylin and impurities. The purification step generally includes (c) adding an aqueous solution of an organic solvent and a basic salt to a second vessel to form a two-phase mixture containing an upper organic phase and a lower aqueous phase; (d) adding a product mixture from a portion of step (b) to the two-phase mixture in step (c) to remove unreacted reactants; (e) removing the lower aqueous phase from the second vessel; (f) treating the upper organic phase with activated carbon; (g) distilling off the organic solvent, leaving tricaprylin and impurities in the second vessel; and (h) recrystallizing the tricaprylin and impurities to remove impurities and form ultra-high purity tricaprylin. Figure 3 illustrates the steps in the overall process. Figure 4 shows in more detail which containers can be used to carry out each step.

[0050]

[0060] In some embodiments, impurities in the product mixture may include unreacted reactants and possibly undesirable by-products. In some embodiments, unreacted reactants may be present in the aqueous phase. reaction process

[0061] In some embodiments, the reaction step includes (a) supplying caprylic acid, concentrated acid, glycerol, and water into a first vessel, and (b) reacting the caprylic acid, concentrated acid, glycerol, and water in the first vessel to form a product mixture containing tricaprylin and impurities. In some embodiments, the supply step may further include supplying caprylic acid and concentrated acid into the first vessel to form a mixture; heating the mixture to a first temperature under an inert atmosphere; and adding glycerol and water to the mixture.

[0051]

[0062] In some embodiments, the reaction step may further include stirring the product mixture at a first temperature for a specified time; removing a first in-process sample from a first container; checking the first in-process sample for conversion; and repeating this step until conversion occurs.

[0052]

[0063] In some embodiments, the vessel may be a conventional reactor, such as a tubular reactor or a tank reactor.

[0064] In some embodiments, the caprylic acid used in this method may be at least about 99% pure. In some embodiments, the caprylic acid has the profile shown in Table 2 below.

[0053] [Table 2]

[0054]

[0065] Similarly, glycerol for use in the disclosed method may be of high purity, for example, at least about 98% pure. In exemplary embodiments, glycerol for use herein has the profile shown in Table 3.

[0055] [Table 3]

[0056]

[0066] The concentrated acid may be selected based on its dehydrating properties. Dehydrating properties can be important in esterification reactions. Water produced as a byproduct of the esterification reaction can be removed through dehydration, shifting the equilibrium of the esterification reaction toward ester formation.

[0057]

[0067] In some embodiments, the acid may be concentrated sulfuric acid, phosphoric acid, or a combination thereof. In some embodiments, the concentrated acid may be sulfuric acid.

[0068] In some embodiments, the concentration of sulfuric acid may be between about 95 wt% and less than about 99.99 wt%. For example, concentrated sulfuric acid may be about 95.1 wt%, about 95.2 wt%, about 95.3 wt%, about 95.4 wt%, about 95.5 wt%, about 95.6 wt%, about 95.7 wt%, about 95.8 wt%, about 95.9 wt%, about 96.0 wt%, about 96.1 wt%, about 96.2 wt%, about 96.3 wt%, about 96.4 wt%, about 96.5 wt%, about 96.6 wt%, about 96.7 wt%, about 96.8 wt%, about 96.9 wt%, about 97.0 wt%, It may also be 97.1 wt%, approximately 97.2 wt%, approximately 97.3 wt%, approximately 97.4 wt%, approximately 97.5 wt%, approximately 97.6 wt%, approximately 97.7 wt%, approximately 97.8 wt%, approximately 97.9 wt%, approximately 99.0 wt%, approximately 99.1 wt%, approximately 99.2 wt%, approximately 99.3 wt%, approximately 99.4 wt%, approximately 99.5 wt%, approximately 99.6 wt%, approximately 99.7 wt%, approximately 99.8 wt%, approximately 99.9 wt%, or approximately 99.99 wt%.

[0058]

[0069] In some embodiments, the first temperature may be in the range of about 90°C to about 120°C. For example, the first temperature may be about 90°C, about 91°C, about 92°C, about 93°C, about 94°C, about 95°C, about 96°C, about 97°C, about 98°C, about 99°C, about 100°C, about 101°C, about 102°C, about 103°C, about 104°C, about 105°C, about 106°C, about 107°C, about 108°C, about 109°C, about 110°C, about 111°C, about 112°C, about 113°C, about 114°C, about 115°C, about 116°C, about 117°C, about 118°C, about 119°C, or about 120°C. In preferred embodiments, the first temperature may be in the range of about 95°C to about 115°C.

[0059]

[0070] In some embodiments, the inert atmosphere may be nitrogen, argon, or a mixture thereof.

[0071] In some embodiments, the first vessel may be maintained at a pressure between approximately 250 mbar and approximately 600 mbar. For example, the pressure may be approximately 260 mbar, approximately 270 mbar, approximately 280 mbar, approximately 290 mbar, approximately 300 mbar, approximately 310 mbar, approximately 320 mbar, approximately 330 mbar, approximately 340 mbar, approximately 350 mbar, approximately 360 mbar, approximately 370 mbar, approximately 380 mbar, approximately 390 mbar, approximately 400 mbar, approximately 410 mbar, approximately 420 mbar, approximately 430 mbar. bar, approximately 440mbar, approximately 450mbar, approximately 460mbar, approximately 470mbar, approximately 480mbar, approximately 490mbar, approximately 500mbar, approximately 510mbar, approximately 520mbar, approximately 530mbar, approximately 540mbar, approximately 550mbar, approximately 560mbar, approximately 570mbar, approximately 580mbar, approximately 590mbar, or approximately 600mbar.

[0060]

[0072] In some embodiments, the ratio of glycerol to water may be in the range of 2:1 to 1:2. For example, this ratio may be about 2:1, about 1.5:1, about 1:1, about 1:1.5, or about 1:2.

[0061]

[0073] In some embodiments, the specified time may be in the range of approximately 2 hours to approximately 17 hours. In some embodiments, the specified time may be in the range of approximately 3 hours to approximately 16 hours. In some embodiments, the specified time may be in the range of approximately 4 hours to approximately 15 hours. In some embodiments, the specified time may be in the range of approximately 5 hours to approximately 14 hours. In some embodiments, the specified time may be in the range of approximately 6 hours to approximately 13 hours. In some embodiments, the specified time may be in the range of approximately 7 hours to approximately 12 hours. In some embodiments, the specified time may be in the range of approximately 8 hours to approximately 11 hours. In some embodiments, the specified time may be in the range of approximately 9 hours to approximately 10 hours. In some embodiments, the specified time may be in the range of approximately 3 hours to approximately 5 hours.

[0062]

[0074] This conversion occurs when the hydroxyl group in glycerol reacts to form an ester group in tricaprylin. After the conversion is achieved, the product mixture can be purified to produce an ultra-high purity composition of tricaprylin.

[0063] Purification process

[0075] In one embodiment, the purification step may include one or more of the following: (c) adding an aqueous solution of an organic solvent and a basic salt to a second vessel to form a two-phase mixture comprising an upper organic phase and a lower aqueous phase; (d) adding a product mixture from the fractionated step (b) to the two-phase mixture in step (c) to remove unreacted reactants; (e) removing the lower aqueous phase from the second vessel; (f) treating the upper organic phase with activated carbon; (g) distilling off the organic solvent and leaving tricaprylin and impurities in the second vessel; and (h) recrystallizing the tricaprylin and impurities to remove impurities and form ultra-high purity tricaprylin. In one embodiment, the purification step may include all of the following: (c) adding aqueous solutions of an organic solvent and a basic salt to a second vessel to form a two-phase mixture comprising an upper organic phase and a lower aqueous phase; (d) adding a product mixture from the fractionated step (b) to the two-phase mixture in step (c) to remove unreacted reactants; (e) removing the lower aqueous phase from the second vessel; (f) treating the upper organic phase with activated carbon; (g) distilling off the organic solvent, leaving tricaprylin and impurities in the second vessel; and (h) recrystallizing the tricaprylin and impurities to remove impurities and form ultra-high purity tricaprylin.

[0064]

[0076] In some embodiments, the product mixture from the first container may be added to the second container. In some embodiments, the purification step may be carried out in the second container. An organic solvent and a basic aqueous solution may be added to the second container. The basic solution may be added to remove excess concentrated acid. The organic solvent may be added to extract organic compounds from the product mixture into the organic phase. These compounds may include tricaprylin, monoesters, diesters, tetraesters, 3-MCPD, 2-MCPD, glycidol, or any combination thereof.

[0065]

[0077] The second container may be maintained at a second temperature. In some embodiments, the second temperature may be in the range of about 25°C to about 50°C. For example, the first temperature may be about 26°C, about 27°C, about 28°C, about 29°C, about 30°C, about 31°C, about 32°C, about 33°C, about 34°C, about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41°C, about 42°C, about 33°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, or about 50°C.

[0066]

[0078] In some embodiments, the second container may be maintained at atmospheric pressure.

[0079] In some embodiments, the organic solvent in step (c) may include an ether. Suitable ethers include, but are not limited to, dimethoxyethane, ditheyl ether, methyl tert-butyl ether, dioxane, THF, 2-methyl THF, CPME, 4-MeTHP, or combinations thereof.

[0067]

[0080] In some embodiments, any suitable basic salt may be used to obtain a basic solution for use in step (c). In some embodiments, the aqueous solution of the basic salt in step (c) may include a solution of sodium carbonate.

[0068]

[0081] In some embodiments, the purification step may further include the step of removing a second in-process sample from a second container and measuring the conductivity of the aqueous layer. The in-process sample may be taken until a desired conductivity is reached. In some embodiments, the desired conductivity may be less than 100 μS / cm.

[0069]

[0082] After reaching the desired conductivity, the product mixture may be subjected to activated carbon treatment. In some embodiments, activated carbon may be added to a second container. The activated carbon treatment may be carried out at room temperature at a rate of 3 g / min.

[0070]

[0083] The next step in the purification process may include removing the organic solvent from the product mixture. In some embodiments, the organic solvent may be removed by distillation. Distillation may be carried out at a third temperature and pressure. In some embodiments, the third temperature may be in the range of about 40°C to about 80°C. For example, the first temperature may be about 40°C, about 41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about 50°C, about 51°C, about 52°C, about 53°C, about 54°C, about 55°C, about 56°C, about 57°C, about 58°C, about 59°C, or about 60°C, about 61°C, about 62°C, about 63°C, about 64°C, about 65°C, about 66°C, about 67°C, about 68°C, about 69°C, about 70°C, about 71°C, about 72°C, about 73°C, about 74°C, about 75°C, about 76°C, about 77°C, about 78°C, about 79°C, or about 80°C. In some embodiments, the pressure may be 1 mbar.

[0071]

[0084] In some embodiments, a second in-process sample may be taken out during the distillation step to measure the amount of organic solvent remaining in the product mixture. Distillation may be continued until the amount of organic solvent in the product mixture is 500 ppm or less. The amount of solvent may be less than about 500 ppm, less than about 400 ppm, less than about 100 ppm, less than about 50 ppm, or less than about 10 ppm.

[0072]

[0085] In some embodiments, the purification step may further include a recrystallization step. In some embodiments, the recrystallization step may include adding a polar solvent to tricaprylin and impurities to form a second mixture comprising the polar solvent, tricaprylin, and impurities; cooling the second mixture to a third temperature; adding a seed crystal to the second mixture to form a third mixture comprising the seed crystal and the second mixture; stirring the third mixture at the third temperature for a third specified time; cooling the third mixture to a fourth temperature for a fourth specified time; maintaining the third mixture at the fourth temperature for a fifth specified time; adding water to the third mixture; maintaining the third mixture at the fourth temperature; filtering the third mixture on a filter cooled to the fourth temperature; washing the third mixture with an aqueous solution of the polar solvent at the fifth temperature; repeating the washing step; collecting tricaprylin crystals; and evaporating the residual solvent from the crystals using a rotary evaporator.

[0073]

[0086] In some embodiments, the recrystallization step may include adding one or more polar solvents to the product mixture and cooling the product mixture to a fourth temperature. In some embodiments, the fourth temperature may be in the range of about -20°C to about 0°C. For example, the first temperature may be about -20°C, about -19°C, about -18°C, about -17°C, about -16°C, about -15°C, about -14°C, about -13°C, about -12°C, about -11°C, about -10°C, about -9°C, about -8°C, about -7°C, about -6°C, about -5°C, about -4°C, about -3°C, about -2°C, about -1°C, or about 0°C.

[0074]

[0087] One or more polar solvents may include water, acetone, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), isopropanol, methanol, or a combination thereof. In some embodiments, one or more polar solvents may be a mixture of water and methanol.

[0075]

[0088] To obtain a composition of ultra-high purity tricaprylin, the solvent may be removed from the product mixture by heating it to a fifth temperature. In some embodiments, the fifth temperature may be in the range of about 40°C to about 80°C. For example, the fifth temperature may be about 40°C, about 41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about 50°C, about 51°C, about 52°C, about 53°C, about 54°C, about 55°C, about 56°C, about 57°C, about 58°C, about 59°C, or about 60°C, about 61°C, about 62°C, about 63°C, about 64°C, about 65°C, about 66°C, about 67°C, about 68°C, about 69°C, about 70°C, about 71°C, about 72°C, about 73°C, about 74°C, about 75°C, about 76°C, about 77°C, about 78°C, about 79°C, or about 80°C. In some embodiments, the pressure may be 1 mbar.

[0076] Mai. Pharmaceutical composition

[0089] Further aspects of the disclosure of the present invention relate to pharmaceutical compositions comprising ultra-high purity tricaprylin provided herein. These pharmaceutical compositions may comprise one or more pharmaceutically appropriate carriers or excipients. The ultra-high purity tricaprylin provided herein may be used as one or more pharmaceutically active ingredients in the pharmaceutical compositions. These pharmaceutical compositions may be used in preventive or therapeutic methods for treating various diseases or disorders as described below herein. Alternatively or additionally, these pharmaceutical compositions may be prepared as food products and / or nutritional compositions, which in some embodiments may be dietary supplements, functional foods, novel foods, food additives, supplements, health foods, power snacks, appetite suppressants, or sports supplements for physical strength and / or endurance. In other cases, the ultra-high purity tricaprylin provided herein may be used as an excipient in pharmaceutical compositions comprising one or more pharmaceutically active ingredients.

[0077] Medicinally acceptable carriers and excipients

[0090] Hereafter, the terms “physiologically acceptable carrier” and “pharmaceutically acceptable carrier,” which can be used interchangeably, refer to a carrier or diluent that does not cause significant irritation to the organism and does not inhibit the biological activity and properties of the administered compound. Adjuvants are included in these terms. In various embodiments, the compositions disclosed herein may further include one or more pharmaceutically acceptable diluents, excipients, or carriers. As used herein, a pharmaceutically acceptable diluent, excipient, or carrier refers to a material suitable for administration to a subject that does not cause undesirable biological effects or adversely interact with any of the components of the composition containing it. Examples of pharmaceutically acceptable diluents, carriers, and excipients include, but are not limited to, physiological salines, Ringer's solution, phosphate solutions or buffers, buffered salines, and other carriers known in the art. Pharmaceutical compositions may also include stabilizers, antioxidants, colorants, other drugs or pharmaceuticals, carriers, adjuvants, preservatives, stabilizers, wetting agents, emulsifiers, solution promoters, salts, solubilizers, defoamers, antioxidants, dispersants, surfactants, and combinations thereof. Herein, the term “excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of the active ingredient. Examples of excipients, but not limited to, include calcium carbonate, calcium phosphate, various sugars and various types of starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Techniques for compounding and administering drugs can be found in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., latest edition (which is incorporated herein by reference).

[0078]

[0091] In various embodiments, the pharmaceutical compositions described herein may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliary agents to facilitate the processing of genetically modified endothelial progenitor cells into preparations that can be used as pharmaceuticals. In other embodiments, any of the well-known techniques, carriers, and excipients may be used as appropriate and as understood in the art.

[0079]

[0092] In various embodiments, the pharmaceutical compositions described herein may be aqueous suspensions containing one or more polymers as suspending agents. In some embodiments, polymers that may constitute the pharmaceutical compositions described herein include water-soluble polymers, e.g., cellulosic polymers, e.g., hydroxypropyl methylcellulose; water-insoluble polymers, e.g., cross-linked carboxyl-containing polymers; mucosal-adhering polymers, e.g., selected from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran; or combinations thereof. In other embodiments, the compositions disclosed herein may contain, as suspending agents, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total weight of the composition. In various embodiments, the pharmaceutical compositions disclosed herein may include viscous formulations. In some embodiments, the viscosity of the composition may be increased by the addition of one or more gelling agents or thickeners. In other embodiments, the compositions disclosed herein may contain one or more gelling agents or thickeners in an amount that results in a formulation sufficiently viscous to remain on the tissue being treated. In yet another embodiment, the compositions disclosed herein may contain at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total weight of the composition of gelling agents or thickeners(s). In yet another embodiment, suitable thickeners may be hydroxypropyl methylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium chondroitin sulfate, or sodium hyaluronate.In other embodiments, viscosity enhancers include acacia (gum arabic), agar, magnesium aluminum silicate, sodium alginate, sodium stearate, bladderwrack, bentonite, carbomer, carrageenan, carbopol, xanthan gum, cellulose, microcrystalline cellulose (MCC), carob (ceratonia), chitin, carboxymethylated chitosan, coriander, dextrose, fercereran, gelatin, gatchigum, guar gum, hectorite, lactose, sucrose, maltodextrin, mannitol, sorbitol, honey, corn starch, wheat starch, rice starch, potato starch, gelatin, karaya gum, xanthan gum, tragacanth gum, ethylcellulose, ethyl hydroxyethylcellulose, ethyl methyl These may be cellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin, polygerin, povidone, propylene carbonate, methyl vinyl ether / maleic anhydride copolymer (PVM / MA), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC), silicon dioxide, polyvinylpyrrolidone (PVP: povidone), Splenda® (dextrose, maltodextrin, and sucralose), or combinations thereof. In some embodiments, a suitable thickener may be carboxymethylcellulose.

[0080]

[0093] In various embodiments, the pharmaceutical compositions disclosed herein may contain additional agents or additives selected from the group including surfactants, surfactants, solvents, acidifiers, alkalizers, buffers, tonicity modifiers, ionic additives effective in increasing the ionic strength of a solution, antimicrobial agents, antibiotics, antifungal agents, antioxidants, preservatives, electrolytes, defoamers, oils, stabilizers, enhancers, and the like. In some embodiments, the pharmaceutical compositions disclosed herein may contain one or more agents in a total amount of at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total weight of the composition. In other embodiments, one or more of these agents may be added to improve the performance, efficacy, safety, shelf life, and / or other properties of the muscarinic antagonist compositions disclosed in the present invention. In embodiments, the additives are expected to be biocompatible and not irritating, abrasive, or allergenic.

[0081]

[0094] In various embodiments, the pharmaceutical compositions disclosed herein may contain one or more acidifying agents. As used herein, “acidifying agent” refers to a compound used to provide an acidic medium. Examples of such compounds include, but are not limited to, acetic acid, amino acids, citric acid, fumaric acid, and other alpha-hydroxy acids, such as hydrochloric acid, ascorbic acid, and nitric acid, as well as others known to those skilled in the art. In some embodiments, any pharmaceutically acceptable organic or inorganic acid may be used. In other embodiments, the compositions disclosed herein may contain one or more acidifying agents in a total amount of at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total weight of the composition.

[0082]

[0095] In various embodiments, the pharmaceutical compositions disclosed herein may contain one or more alkalizing agents. As used herein, “alkalizing agent” refers to a compound used to provide an alkaline medium. Examples of such compounds include, but are not limited to, ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium bicarbonate, sodium hydroxide, triethanolamine, and trolamine, as well as others known to those skilled in the art. In some embodiments, any pharmaceutically acceptable organic or inorganic base may be used. In other embodiments, the compositions disclosed herein may contain one or more alkalizing agents in a total amount of at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total weight of the composition.

[0083]

[0096] In various embodiments, the pharmaceutical compositions disclosed herein may contain one or more antioxidants. As used herein, “antioxidant” means an agent that can be used to inhibit oxidation and thereby prevent deterioration of the preparation by an oxidation process. Examples of such compounds include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylhydroxyanisole, butylhydroxytoluene, hypophophorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, and sodium pyrosulfite, as well as other materials known to those skilled in the art. In some embodiments, the compositions disclosed herein may contain one or more antioxidants in a total amount of at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total weight of the composition.

[0084]

[0097] In other embodiments, the pharmaceutical compositions disclosed herein may include a buffer system. As used herein, “buffer system” is a composition comprising one or more buffering agents, where “buffering agent” is a compound used to minimize pH changes during dilution or the addition of an acid or alkali. Examples of buffering agents include, but are not limited to, potassium metaphosphate, potassium phosphate, monobasic sodium acetate, and sodium citrate anhydrous and dihydrate, as well as other materials known to those skilled in the art. In some embodiments, any pharmaceutically acceptable organic or inorganic buffer may be used. In another embodiment, the compositions disclosed herein may contain one or more buffering agents in a total amount of at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total weight of the composition. In other embodiments, the amount of one or more buffering agents may depend on the desired pH level of the composition. In some embodiments, the pharmaceutical compositions disclosed herein may have a pH of about 6 to about 9. In other embodiments, the pharmaceutical compositions disclosed herein may have a pH greater than about 8, greater than about 7.5, greater than about 7, greater than about 6.5, or greater than about 6. In preferred embodiments, the compositions disclosed herein may have a pH greater than about 6.8.

[0085]

[0098] In various embodiments, the pharmaceutical compositions disclosed herein may contain one or more preservatives. As used herein, “preservative” means an agent or combination of agents that inhibits, reduces, or eliminates the growth of bacteria in the pharmaceutical dosage form. Non-limiting examples of preservatives include nipagin, nipasol, isopropyl alcohol, and combinations thereof. In some embodiments, any pharmaceutically acceptable preservative may be used. In other embodiments, the pharmaceutical compositions disclosed herein may contain one or more preservatives in a total amount of at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total weight of the composition.

[0086]

[0099] In other embodiments, the pharmaceutical compositions disclosed herein may contain one or more surfactants or surface-active reagents. In some embodiments, the surfactants or surface-active reagents may be synthetic, natural, or semi-synthetic. In other embodiments, the compositions disclosed herein may contain anionic surfactants, cationic surfactants, zwitterionic surfactants, amphoteric electrolyte surfactants, amphoteric surfactants, nonionic surfactants, or combinations thereof, having a steroid skeleton. In yet another embodiment, the pharmaceutical compositions disclosed herein may contain one or more surfactants or surface-active reagents in a total amount of at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total weight of the composition.

[0087]

[0100] In various embodiments, the pharmaceutical compositions disclosed herein may contain one or more stabilizers. As used herein, “stabilizer” means a compound used to stabilize an active agent against physical, chemical, or biochemical processes that, if not stabilized, would reduce the therapeutic activity of the agent. Suitable stabilizers include, but are not limited to, succinic anhydride, albumin, sialic acid, creatinine, glycine and other amino acids, niacinamide, sodium acetyltryptophonate, zinc oxide, sucrose, glucose, lactose, sorbitol, mannitol, glycerol, polyethylene glycol, sodium caprylate and sodium saccharin, and others known to those skilled in the art. In some embodiments, the pharmaceutical compositions disclosed herein may contain one or more stabilizers in a total amount of at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total weight of the composition.

[0088]

[0101] In other embodiments, the pharmaceutical compositions disclosed herein may contain one or more isotonic agents. As used herein, “isotonic agent” refers to a compound that can be used to adjust the tension of a liquid formulation. Suitable isotonic agents include, but are not limited to, glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, sorbitol, trehalose, and those known to those skilled in the art. The osmotic molar concentration of a composition may be expressed in milliosmoles per liter (mOsm / L). The osmotic molar concentration may be measured using methods generally known in the art. In preferred embodiments, the vapor pressure lowering method is used to calculate the osmotic molar concentration of the compositions disclosed herein. In some embodiments, the amount of one or more isotonic agents constituting the pharmaceutical composition disclosed herein may be such that the osmotic molar concentration of the composition is about 150 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 350 mOsm / L, about 280 mOsm / L to about 370 mOsm / L, or about 250 mOsm / L to about 320 mOsm / L. In other embodiments, the compositions described herein may have osmotic molar concentrations in the range of about 100 mOsm / kg to about 1000 mOsm / kg, about 200 mOsm / kg to about 800 mOsm / kg, about 250 mOsm / kg to about 500 mOsm / kg, or about 250 mOsm / kg to about 320 mOsm / kg, or about 250 mOsm / kg to about 350 mOsm / kg, or about 280 mOsm / kg to about 320 mOsm / kg. In some embodiments, the pharmaceutical compositions described herein have an osmotic molar concentration of about 100 mOsm / L to about 1000 mOsm / L, about 200 mOsm / L to about 800 mOsm / L, about 250 mOsm / L to about 500 mOsm / L, about 250 mOsm / L to about 350 mOsm / L, about 250 mOsm / L to about 320 mOsm / L, or about 280 mOsm / L to about 320 mOsm / L.In further embodiments, the pharmaceutical compositions disclosed herein may contain one or more tonicity modifiers in a total amount of at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% of the total weight of the composition.

[0089] Administration formulation

[0102] Appropriate routes of administration may include, for example, oral, rectal, transmucosal, and especially nasal, intestinal, or parenteral delivery (including intramuscular, subcutaneous, and intrathecal injections, as well as intravenous, intraperitoneal, intranasal injections, intraocular (e.g., via eye drops), or topical (e.g., creams or ointments)). The tricaprlin disclosed herein is of ultra-high purity and is therefore particularly suitable for oral administration.

[0090]

[0103] The pharmaceutical compositions disclosed in the present invention may be manufactured by processes well known in the art, for example, by conventional processes such as mixing, dissolving, granulation, sugar-coating, polishing, emulsification, capsule filling, encapsulation, or freeze-drying.

[0091]

[0104] Therefore, the pharmaceutical compositions for use according to the disclosure of the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers, which include excipients and adjuvants that facilitate the processing of the active ingredient into a preparation that can be used as a pharmaceutical. The appropriate formulation depends on the selected route of administration.

[0092]

[0105] A pharmaceutical composition suitable for use in the context of the disclosure of this invention includes a composition containing an active ingredient in an amount effective to achieve the intended purpose. In some embodiments, a therapeutically effective amount means an amount of the active ingredient (i.e., ultra-high-purity tricaprylin as disclosed herein) that is effective in preventing, delaying, alleviating, or improving the symptoms of a disorder to be treated, or in extending its survival time.

[0093]

[0106] Determining the therapeutically effective dose is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0107] For any preparation used in the methods disclosed herein, the therapeutically effective dose or amount can be initially estimated from in vitro and in vivo assays and / or screening platforms disclosed herein. For example, the dose can be formulated to achieve a desired concentration or potency in an animal model. Using such information, a useful dose in humans can be more accurately determined.

[0094]

[0108] The toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell culture, or in laboratory animals. Data obtained from these in vitro and cell culture assays, as well as from animal studies, can be used to formulate a range of dosages for human use. Dosages may vary depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration, and dosage can be selected by individual physicians in consideration of the patient's condition.

[0095]

[0109] The dosage and dosing interval may be individually adjusted to achieve a sufficient intracerebral or blood level of the active ingredient (minimum effective concentration, MEC) to induce or inhibit a biological effect. While the MEC will vary for each preparation, it can be estimated from in vitro data. The dosage required to achieve the MEC will depend on the individual characteristics and route of administration. Detection assays can be used to determine plasma concentrations.

[0096]

[0110] Depending on the severity and responsiveness of the condition being treated, the medication may be administered as a single dose or multiple doses, and the treatment process may continue for several days to several weeks, or until the treatment becomes effective or the condition is alleviated. The amount of the composition to be administered will naturally depend on the subject being treated, the severity of the disease, the mode of administration, and the judgment of the prescribing physician. The effective dose may be extrapolated from dose-response curves derived from in vitro or in vivo testing systems.

[0097] IV. Treatment Methods

[0111] As described above, the disclosure of the present invention provides an ultra-high purity composition of tricaprylin. This ultra-high purity composition is particularly suitable for applications requiring high purity quality and high levels of active ingredients, such as nutritional and pharmaceutical applications and uses (e.g., application at high doses and / or high concentrations).

[0098]

[0112] Therefore, in various embodiments, methods are provided for treating subjects requiring treatment. In some embodiments, methods are provided for treating diseases in subjects preventively or therapeutically. In some embodiments, the diseases to be treated (preventively or therapeutically) are disorders of energy metabolism, particularly ketone body metabolism, e.g., cranial trauma, stroke, hypoxia; cardiovascular diseases, e.g., myocardial infarction, refeeding syndrome, anorexia, epilepsy; neurodegenerative diseases, e.g., dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis; lipid metabolism disorders, e.g., glucose transporter deficiency (GLUT1 deficiency), VL-FAOD, and mitochondrial diseases, e.g. This may be related to mitochondrial thiolase deficiency, Huntington's disease, cancer, e.g., T-cell lymphoma, astrocytoma, and glioblastoma, HIV, rheumatic diseases, e.g., rheumatoid arthritis, and gout, gastrointestinal diseases, e.g., chronic inflammatory bowel disease, in particular ulcerative colitis, and Crohn's disease, lysosomal storage disorders, e.g., sphingolipidosis, in particular Niemann-Pick disease, diabetes mellitus, migraine and migraine headache, epilepsy, in particular infantile spasms, and the effects or side effects of chemotherapy. In some embodiments, methods for administering prophylactic or therapeutic measures for Alzheimer's disease, in particular mild to moderate forms of Alzheimer's disease; migraine and migraine headache; and epilepsy, in particular infantile spasms, in subjects in need.

[0099]

[0113] As stated above, a pharmaceutical composition comprising ultra-high purity tricaprylin is provided for use in the prophylactic or therapeutic treatment of subjects having a disease, wherein the disease is a disorder of energy metabolism, in particular ketone body metabolism, e.g., cranial trauma, stroke, hypoxia; cardiovascular disease, e.g., myocardial infarction, refeeding syndrome, anorexia, epilepsy; neurodegenerative disease, e.g., dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis; lipid metabolism disorder, e.g., glucose transporter deficiency (GLUT1 deficiency), VL- FAOD, and mitochondrial diseases, e.g., mitochondrial thiolase deficiency, Huntington's disease, cancer, e.g., T-cell lymphoma, astrocytoma, and glioblastoma, HIV, rheumatic diseases, e.g., rheumatoid arthritis, and gout, gastrointestinal diseases, e.g., chronic inflammatory bowel disease, in particular ulcerative colitis, and Crohn's disease, lysosomal storage disorders, e.g., sphingolipidosis, in particular Niemann-Pick disease, diabetes mellitus, migraine and migraine headache, epilepsy, in particular infantile spasms, and the effects or side effects of chemotherapy. In some embodiments, pharmaceutical compositions comprising ultra-high purity tricaprylin are provided for use in providing prophylactic or therapeutic treatment for Alzheimer's disease, in particular mild to moderate forms of Alzheimer's disease; migraine and migraine headache; and epilepsy, in particular infantile spasms, in subjects where it is needed.

[0100]

[0114] As described above, in some embodiments, high doses of ultra-high purity tricaprlin are administered to subjects in need. The high dose may be administered by any of the above-described formulations. In certain embodiments, the high dose may be administered orally. In some embodiments, the high dose may be administered systemically. In some embodiments, a suitable dosing plan may include administering at least about 20 mg / day to about 100 mg / day of ultra-high purity tricaprlin to subjects in need. In some embodiments, a suitable dosing plan may include administering at least 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, or 40 mg of tricaprlin per day. The tricaprylin composition may be combined with appropriate excipients or other active ingredients so that the total amount of tricaprylin ingested per day is in the range of 20 mg / day to 100 mg / day. Furthermore, the dose may be administered in several divided doses and staggered doses daily or sequentially, or the dose may be infused continuously or as a bolus. In addition, the dosage of the compound(s) described herein may be increased or decreased proportionally as indicated by the urgency of the therapeutic or preventive situation. The selected dosage level will depend on a variety of factors, including the route of administration, time of administration, and rate of elimination, duration of treatment, other drugs, compounds, and / or materials used in combination with the specific compound used, age, sex, weight, condition, overall health, and medical history of the patient to be treated, as well as similar factors well known in the medical field.

[0101]

[0115] A physician or veterinarian with ordinary skill in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the compound described herein used in the pharmaceutical composition at a level lower than the level required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0102]

[0116] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six, or more adjunct doses, administered separately at appropriate intervals throughout the day, and possibly in unit dosage form. Similarly, the daily dose may be administered for any appropriate duration, e.g., at least one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, or longer.

[0103]

[0117] The compounds described herein can be administered alone, but may also be administered in combination with other active compositions.

[0118] The term “combination” means either a combination fixed to a single unit dosage form, or a kit of parts for concomitant administration (in which case the compositions and their partners described herein may be administered simultaneously and independently, or separately within a time interval, particularly within a time interval that allows the partners to exert a cooperative, for example, synergistic effect), or any combination thereof. The compositions described herein may be administered simultaneously or sequentially with anti-inflammatory agents, antiproliferative agents, antibiotics, NSAIDs, analgesics, chemotherapeutic agents, immunosuppressants, other anticancer agents, cytotoxic agents, or salts thereof.

[0104]

[0119] Those skilled in the art can modify and change aspects of the invention without departing from the scope of the invention as defined in the appended claims, as can be seen from the above-mentioned detailed description, as well as from the drawings and claims. [Examples]

[0105] Example 1: Experiment

[0120] Tricaprylin is synthesized by condensing glycerol with 3 equivalents of octanoic acid (caprylic acid) (used in excess) under acidic conditions. The octanoic acid is treated with concentrated H2SO4, and the mixture is heated to approximately 115°C. Glycerol is slowly added, and the mixture is stirred overnight. The mixture is then cooled to room temperature and diluted with MTBE (or an alternative solvent that does not yield methyl esters in subsequent batches). The solution is then filtered over activated carbon for decolorization. The organic phase is washed several times with aqueous Na2CO3 to deplete any remaining octanoic acid and concentrated H2SO4, and then extracted with water to remove any residual salts. The MTBE is then removed under reduced pressure to obtain tricaprylin as a clear, colorless liquid (see Figure 5).

[0106]

[0121] Experiments were conducted to test the significance of various parameters, and novel steps were included to improve sample yield and purity. Table 4 shows a description and analysis of the experiments performed, as well as the results obtained. In the following examples, conclusions from these experimental groups are explained, and some unexpected properties of the findings are described in detail.

[0107] [Table 4-1]

[0108] [Table 4-2]

[0109] [Table 4-3]

[0110] [Table 4-4]

[0111] [Table 4-5]

[0112] Table 4-6

[0113] Table 4-7

[0114] Table 4-8

[0115] Table 4-9

[0116] Table 4-10

[0117] Table 4-11

[0118] Table 4-12

[0119] Table 4-13

[0120] Table 4-14

[0121] Table 4-15

[0122] Table 4-16

[0123] Table 4-17

[0124] Table 4-18

[0125] Table 4-19

[0126] Table 4-20

[0127] Table 4-21

[0128] Table 4-22

[0129] Table 4-23

[0130] Table 4-24

[0131] Table 4-25

[0132] Table 4-26

[0133] Table 4-27

[0134] Table 4-28

[0135] Table 4-29

[0136] Table 4-30

[0137] Table 4-31

[0138] Table 4-32

[0139] Table 4-33

[0140] Table 4-34

[0141] Table 4-35

[0142] Table 4-36

[0143] Table 4-37

[0144] Example 2: Minimizing the condensation of caprylic acid on a condenser

[0122] In the initial experiments (EXP-23-AA6314, EXP-23-AA6315, EXP-23-AA6317, EXP-23-AA6318, EXP-23-AA6319), undesirable condensation of caprylic acid was observed on the condenser between the reactor and the water receiving flash. This phenomenon was considered serious because it not only reduced the amount of reagent available for the reaction but also led to temporary blockage of the vacuum line (as in EXP-23-AA6317), reduced the effectiveness of water removal, and could potentially lead to dangerous reactor overpressure caused by the nitrogen inlet. This observation was unexpected because the boiling point of the reagent at different pressure values ​​(reported in Table 2) was always above the reaction temperature.

[0145]

[0123] In an attempt to solve this problem, we tested adding a pre-mixed mixture of glycerol and octanoic acid (EXP-23-AA6320). This reduced the total residence time of caprylic acid in the reactor. However, this method did not prevent condensation of the reagent on the condenser, and in addition, due to the low miscibility of these reagents, a two-phase mixture was formed during addition and reaction.

[0146]

[0124] Reducing the nitrogen flow from 60 NL / h to 6 NL / h was not sufficient to solve this problem (EXP-23-AA6320). Surprisingly, the importance of the apparatus's shape was suggested by using an apparatus with longer tubes, for example, a Dean-Stark apparatus instead of a Diemroth condenser (EXP-23-AA-8203). Using a Dean-Stark apparatus increased the path the vapor traveled before reaching the condenser, and consequently, the caprylic acid recondensed in the reaction mixture before leaving the reactor and reaching the condenser. Water, on the other hand, is volatile enough to be removed from the reaction mixture at a given temperature and pressure. In almost all experiments using a Dean-Stark apparatus, the amount of caprylic acid recollected in addition to the water released from the reaction was only about a few mL, confirming that there was excess caprylic acid in the reactor. A diagram of the apparatus used is reported in Figure 6.

[0147] Example 3: Maximizing conversion to product Method of adding glycerol: from above

[0125] If no chemicals leave the reactor, the reaction can proceed and be completed by the stepwise formation of monoesters, diesters, and finally the product, glyceryl trioctanoate. The limiting reagent, glycerol, was added from above to a mixture of octanoic acid and sulfuric acid that was being stirred and heated. The addition rate under these conditions greatly affected the formation of the tetraester, and this impurity was quantified above the initially defined limit of 0.4% in almost all experiments. Even reducing the catalyst input to 0.5% was insufficient to reach the defined limit (see Table 6).

[0148] [Table 5]

[0149]

[0126] Experiments in which the tetraester level fell below the initial requirement of 0.4% are listed in the last items 8 and 9. Generally, the reactor head in laboratory-scale reactors requires additional heating due to its distance from the heated jacket. In the absence of this additional heating, the water produced from the reaction is removed more slowly, inhibiting tetraester formation (EXP-23-AA8211). In addition, if the reaction temperature is reduced to 95°C and the rate of pure glycerol addition is reduced to 1 mL / hour, the reaction proceeds with the formation of negligibly small amounts of byproducts (EXP-23-AA8212).

[0150] Method of adding glycerol: from above

[0127] Unexpectedly, adding glycerol from below the reaction surface improved mixing with the reactants, thereby reducing tetraester formation. In all experiments conducted using this addition method, tetraester levels were below 0.5%. Adding glycerol directly to the reaction mixture increased the overall robustness of the reaction. Rapid addition did not significantly increase the byproduct (EXP-23-AA8208), and increasing the catalyst input to 4.5% mol only moderately increased the tetraester (EXP-23-AA8206). In this case, lowering the catalyst input had virtually no significant effect (EXP-23-AA6326). Temperature also did not appear to be very important. Similar results in terms of yield and purity were obtained when the reaction was carried out at 115, 105, or 95°C. Surprisingly, rapid addition, which lowered the reaction temperature from 115°C to 105°C (EXP-23-AA8210), had a small but positive effect on byproduct formation, but did not affect conversion. Simultaneous reduction of temperature and catalytic yield did not significantly alter the product purity profile or final yield (EXP-23-AA6327). Unexpectedly, in this case, the tetraester detected in the final product was relatively high compared to other experiments in this series (Table 7).

[0151] [Table 6]

[0152] Method of adding glycerol: Upward but diluted

[0128] To allow for administration from above while keeping the tetraester level low, it was reasonable to consider that reducing the initial concentration of glycerol would reduce the likelihood of acid-catalyzed ether formation. Therefore, glycerol was diluted with an equivalent amount of water and then added to the reaction. The additional water was to be removed as well as the water formed during the reaction to tricaprylin. This method resulted in better control of tetraester formation in all experiments, as summarized in the following table.

[0153]

[0129] The results suggest that tetraester formation can be minimized by using a low administration rate (EXP-23-AA6328). Increasing the administration rate (EXP-23-AA3527 or EXP-23-AA6332) or decreasing the amount of catalyst added (EXP-23-AA358214) does not improve the quality of the material. A non-extensive list of experiments using this administration method is summarized in Table 8.

[0154] [Table 7]

[0155] Other acid catalysts

[0130] As a substitute for sulfuric acid used in other experiments, phosphoric acid (85%) was tested. Conversion to the product was much slower, and after nearly 23 hours of reaction at 100°C and subsequent work-up, analysis of the isolated material showed 75% a diester and only 20% of the product (EXP-23-AA6330).

[0156] [Table 8]

[0157]

[0131] The amount of glycidol is affected by a combination of different parameters, such as the quality of the starting materials, as well as the reaction conditions applied. Generally, its formation requires harsh conditions to form a distorted three-membered ring of epoxide. As observed in a few experiments, increasing the reaction temperature was associated with an increase in glycidol levels (EXP-23-AA6319 and EXP-23-AA8206).

[0158]

[0132] Further consideration can be made as follows. When the conditions are made milder (EXP-23-AA8212) and the addition of glycerol is delayed (EXP-23-AA8209), its formation is reduced, but if the amount of catalyst added is increased, glycidol is formed even if the addition is delayed (EXP-23-AA8206) or even if high temperature is applied (EXP-23-AA6319 and EXP-23-AA8206). It appears that reducing the amount of catalyst added has a beneficial effect even when the administration rate is slightly increased (EXP-23-AA6322 and AA6324).

[0159]

[0133] Interestingly, mixing glycerol with water is useful in reducing glycidol formation, and increasing the administration rate does not appear to correlate with an increase in this by-product (EXP-23-AA6328 and EXP-23-AA8214).

[0160]

[0134] While certain trends can be identified, it is worth noting that these values ​​are not always consistent due to the extremely small quantities examined and the high sensitivity of the measurements. These results are summarized in Table 10 below.

[0161] [Table 9]

[0162] Example 4: Work-up Procedure

[0135] During workup, the reaction mixture can be washed away by treating it with a basic aqueous solution to quench its acidity and convert excess octanoic acid into more water-soluble sodium octanoate. Experiments were conducted to test various workup procedures.

[0163] different bases

[0136] In addition to sodium carbonate, which is used intensively, sodium bicarbonate was also evaluated. NaOH was not tested because it increases the risk of saponification that occurs when esters are treated with such a reagent. The experimental results showed that sodium bicarbonate does not immediately remove excess fatty acids, thereby resulting in a very high acid value in the final product. Table 11 shows a comparison between these two reagents.

[0164] [Table 10]

[0165]

[0137] The effects of different basic washing solutions, such as K2CO3, KHCO3, and NaHCO3, at 40°C on the removal of glycidol and MCPD were also evaluated. The results are summarized in Table 12.

[0166] [Table 11]

[0167]

[0138] The different bases tested did not affect the removal of MCPD and had little effect on the amount of glycidol. Considering that the effectiveness of sodium bicarbonate is reduced in the removal of excess octanoic acid during workup, sodium carbonate was identified as the optimal base. different solvents

[0139] Next, the organic solvents used in the workup were examined. The reaction product was divided into two fractions, and the same procedure was applied to both fractions. The performance of toluene and heptane was compared, and the results are summarized in Table 13.

[0168] [Table 12]

[0169]

[0140] No change in the purity profile of the sample was observed. Therefore, it can be concluded that both are equally appropriate.

[0170] Without solvent

[0141] A workup without any additional organic solvents was also attempted (EXP-23-AA6318). In this case, different washing solutions were tested: (a) using a mixture of saturated NaCl and 10% Na2CO3, very good phase separation was obtained in seconds. The presence of a large amount of salt ensured rapid phase separation and a clear phase; (b) the crude reaction product was treated with a saturated aqueous solution of NaCl following a basic wash. Phase separation was very good and achieved within seconds; and (c) the organic residue was washed with water alone. In this case, after 30 minutes the organic layer was still turbid and contained a large amount of water.

[0171]

[0142] It was concluded that if no organic solvent is present during workup, a strong ionic aqueous phase (e.g., NaCl solution) is necessary to achieve satisfactory phase separation.

[0172] Example 5: Purification

[0143] After work-up, the material can be further processed to improve its appearance, odor, or purity profile. Different materials and techniques were tested and evaluated.

[0173] activated carbon

[0144] Treatment with activated carbon can remove impurities from the material and improve its appearance. Different types of activated carbon were tested under different conditions. The results are summarized in Table 14.

[0174] [Table 13]

[0175]

[0145] The best results were obtained by treating concentrated tricaprylin samples with CARBOFIL CA at room temperature (EXP-23-AA5430). The same material did not perform similarly when the temperature was raised to 70°C, which may have been caused by a tenfold increase in the processing volume (EXP-23-AA5433), thereby saturating the pad. Treatment of tricaprylin with BECODISC reduced glycidol levels and, surprisingly, significantly increased the amount of MCPD. Tricaprylin was also treated with Celite and powdered activated carbon overnight at 110°C. The results are shown in Table 15.

[0176] [Table 14]

[0177]

[0146] Interestingly, this treatment significantly reduced the glycidol content. It was observed that neither the quality of the material nor the amount of chlorinated by-products was affected. In conclusion, treatment of concentrated tricaprylin with activated carbon at room temperature can significantly reduce the amount of glycidol in the sample (EXP-23-AA4115-4 and EXP-23-AA5430). Unfortunately, none of the experiments affected the MCPD species.

[0178] Diatomaceous earth

[0147] Similar to activated carbon, diatomaceous earth is widely used as a filter aid or adsorbent due to its high porosity and low density. Different types of materials and conditions were tested. The results are summarized in Table 16.

[0179] [Table 15]

[0180]

[0148] The general trend observed is that the effectiveness of glycidol removal in all these materials increases with temperature. The amount of MCPD remained essentially unchanged. The material that showed a greater extension of glycidol removal in the presence of activated carbon and at high temperatures was the so-called "fuller soil" (EXP-23-AA6331).

[0181]

[0149] Another series of commercially available diatomaceous earth samples were tested (EXP-23-AA3529). Generally, this treatment resulted in a good reduction in glycidol content, with the best results obtained with Tonsil210FF. The MCPD species remained unchanged after all treatments. Steam distillation

[0150] To remove volatile components such as odor, steam distillation was tested by treating the material with a steam stream under reduced pressure. When a 51g sample of tricaprylin was treated with 500mL of water at 130°C at a flow rate of 10mL / min, the amount of glycidol decreased significantly, as summarized in Table 17.

[0182] [Table 16]

[0183]

[0151] Steam distillation appears to be a suitable method for efficiently removing glycidol from tricaprylin samples. MCPD levels remain unchanged. The purity profile remains equivalent after processing. Ion exchange

[0152] In an attempt to reduce the amounts of MCPD and glycidol in isolated tricaprylin, the material was treated with different ion exchange resins under different conditions. The results are summarized in Table 18.

[0184] [Table 17]

[0185]

[0153] Using anion exchange resin resulted in a decrease in glycidol, but with a slight increase in MCPD species. The cation exchange resin used in EXP-23-AA3252-3 did not appear to be a suitable candidate for removing these impurities. Despite positive results with the anion exchange resin, its removal capacity was insufficient to achieve single-digit ppb glycidol levels.

[0186]

[0154] The same resin was tested at a higher temperature (70°C), but with a reduced reaction time (2 hours). The results are summarized in Table 19.

[0187] [Table 18]

[0188]

[0155] Despite the observation of a decrease in the amount of glycidol in three experiments, the amounts of 3-MCPC and 2-MCPD remained more or less constant. Overall, treating tricaprylin with ion exchange resin at high temperatures does not appear to be a worthwhile option. Short-step distillation

[0156] Tricaprylin was subjected to short-pass distillation at a jacket temperature of 130°C and a reduced pressure of 4 mbar. Subsequently, the MCPD and glycidol profiles of the samples were analyzed as summarized in Table 20.

[0189] [Table 19]

[0190]

[0157] Considering the increase in glycidol levels after processing, the use of short-pass distillation cannot be recommended as a purification method.

[0191] recrystallization

[0158] Tricaprylin can be recrystallized from MeOH at temperatures close to 0°C. The presence of water as a poor solvent is beneficial to this process in terms of yield and purity.

[0192]

[0159] Generally, the product was mixed with MeOH (8 volumes) and cooled to 0 °C. Added to the seed crystal, and then controlled cooling was carried out from 0 °C to -10 °C within 3 hours. Water (1 volume) was slowly added to the cold mixture, and it was stirred for another 1 hour. Then the crystals were filtered on a cooled filter and washed with a cold mixture of MeOH / water (9:1). The crystals were collected and the solvent was removed with a rotary evaporator. The setup used is shown in Figure 7 and the results are shown in Table 21.

[0193]

Table 20-1

[0194]

Table 20-2

[0195]

Table  20-3

[0196]

[0160] After optimizing the crystallization conditions, it was possible to obtain a 50 g scale material with extremely high and stable purity (99% a or higher). As shown in the table above, this technique enables the removal of not only diesters, tetraesters but also MCPD and glycidol (below the detection limit of 100 ppb).

[0197] Example 6: Exemplary Workflow

[0161] Glycerol was obtained from Verbio. Caprylic acid was obtained from Fisher Scientific. Na2CO3 was obtained from Thermo Scientific. Concentrated sulfuric acid was obtained from Merck. The chloride content in all reactants was below <10 ppm or undetectable.

[0198]

[0162] Figure 9 shows the process for preparing an ultra-high purity composition of tricaprylin. Caprylic acid (99.6% purity) and concentrated sulfuric acid (96%) were added to the first container. The container was heated to 100°C and pressurized to 500 mbar under a nitrogen stream. Glycerol (>99.5%) and water in a 1:1 ratio were added to the first container and stirred. This container was maintained at 100°C and 500 mbar. An in-process sample was taken from the container and checked for conversion. After conversion was observed, a portion of the reaction mixture from container 1 was added to the second container. Aqueous solutions of MTBE (>99%) and Na2CO3 (>99%) were also added to the second container and the container was heated to 40°C. The pressure in the second container was 1 atm. The contents of the second container were stirred and the aqueous phase was discharged. The second portion of the reaction mixture from container 1 was added to container 2, and aqueous solutions of MTBE and Na2CO3 were added to container 2. The container was maintained at 40°C and 1 atm. The contents of the second container were stirred, and the aqueous phase was drained. Additional water was added to container 2, and the container was maintained at 40°C and 1 atm. The aqueous phase was drained. The in-process sample was taken from container 2, and its conductivity was measured. The addition of water, stirring, and removal of the aqueous phase were continued until the conductivity of the aqueous phase was less than 100 μS / cm. After reaching the desired conductivity, activated carbon was added to the second container, and the residual organic phase was treated with activated carbon at 3 g / min. The activated carbon treatment was carried out at room temperature. After the activated carbon treatment, the MTBE was removed by distillation by heating the second container to 50°C and applying a pressure of 1 mbar. The in-process sample was tested for MTBE by gas chromatography. Distillation was continued until the amount of residual MTBE was 500 ppm. The residual product mixture was recrystallized by cooling the container to a temperature between -10°C and approximately 0°C. After recrystallization, all residual solvents were removed by heating the container to 50°C and reducing the volume to 1 mbar. The obtained product was analyzed by gas chromatography.

[0199]

[0163] Table 22 shows the results for six batches of tricaprylin produced by the exemplary procedure. Figures 8A–8D show the CG-MS analysis of the products.

[0200] Table 21

Claims

1. An ultra-high purity composition comprising at least about 99.2% by weight of tricaprylin and about 0.8% by weight or less of impurities, Tricaprylin is the tricaprylin of triesters; The impurity contains one or more of the following: 2-monochloropropanediol, 2-monochloropropanediol monoester, 2-monochloropropanediol diester, 3-monochloropropanediol, 3-monochloropropanediol monoester, 3-monochloropropanediol diester, or any combination thereof. Ultra-high purity composition.

2. The ultra-high purity composition according to claim 1, comprising at least about 99.5% by weight of tricaprylin and about 0.5% by weight or less of impurities.

3. The ultra-high purity composition according to claim 1, comprising at least about 99.7% by weight of tricaprylin and about 0.3% by weight or less of impurities.

4. The ultra-high purity composition according to claim 1, wherein 3-monochloropropanediol, 3-monochloropropanediol monoester, and 3-monochloropropanediol diester are present at a concentration of 35 ppb or less.

5. The ultra-high purity composition according to claim 1, comprising, respectively, 3-monochloropropanediol and 3-monochloropropanediol diester at concentrations of less than 35 ppb.

6. The ultra-high purity composition according to claim 1, further comprising glycidol, a monoester tricaprylin, a diester tricaprylin, or a tetraester tricaprylin as an impurity.

7. The ultra-high purity composition according to claim 6, further comprising glycidol with an impurity content of less than 35 ppb.

8. The ultra-high purity composition according to claim 1, wherein the impurities further include unreacted reactants.

9. A method for producing an ultra-high purity composition of tricaprylin, (a) A step of supplying caprylic acid, concentrated acid, glycerol, and water into the first reactor; (b) A step of reacting caprylic acid, concentrated acid, glycerol, and water in a first reactor to form a product mixture containing tricaprylin and impurities, wherein the impurities contain unreacted reactants and possibly undesirable by-products; (c) Adding an aqueous solution of an organic solvent and a basic salt to a second reactor to form a two-phase mixture comprising an upper organic phase and a lower aqueous phase; (d) A step of removing unreacted reactants by adding a product mixture from step (b) to the two-phase mixture in step (c), wherein the unreacted reactants are present in the aqueous phase; (e) The step of removing the lower aqueous phase from the second reactor; (f) A step of treating the upper organic phase with activated carbon; (g) a step of removing the organic solvent by distillation, leaving tricaprylin and impurities in the second reactor; and (h) A process to recrystallize tricaprylin and impurities to remove impurities and form ultra-high purity tricaprylin. Methods that include...

10. Step (a) is, (a) A step of supplying caprylic acid and concentrated acid together into a first reactor to form a mixture; (aii) A step of heating the mixture to a first temperature under an inert atmosphere; and (aiii) A step of adding glycerol and water to the mixture over a first specified time. The method according to claim 9, further comprising:

11. Step (b) is, (bi) A step of stirring the product mixture at a second temperature for a second specified time; (biii) Step of removing the first in-process sample from the first reactor; (biii) A step of checking a first in-process sample for conversion, wherein the conversion is the reaction of a hydroxyl group in glycerol to an ester group in tricaprylin; and (biv) A process that repeats from process (bii) to process (biii) until conversion occurs. The method according to any one of claims 9 to 10, further comprising:

12. Step (g) is, (gi) Step of removing the second in-process sample from the second reactor; (gii) A step of measuring the amount of organic solvent remaining in tricaprylin and impurities; and (giiii) A process in which steps (gi) to (gii) are repeated until the amount of residual organic solvent is 500 ppm or less. The method according to any one of claims 9 to 11, further comprising:

13. Process (h) is, (hi) A step of adding a polar solvent to tricaprylin and impurities to form a second mixture containing the polar solvent, tricaprylin, and impurities; (hii) A step of cooling the second mixture to a third temperature; (hiiii) A step of adding seed crystals to the second mixture to form a third mixture containing seed crystals and the second mixture; (HIV) A step of stirring the third mixture at a third temperature for a third specified time; (hv) A step of cooling the third mixture to a fourth temperature for a fourth specified time; (hvi) A step of maintaining the third mixture at a fourth temperature for a fifth specified time; (hvii) The step of adding water to the third mixture; (hviii) A step of maintaining the third mixture at a fourth temperature; (hix) The third mixture is filtered on a filter cooled to a fourth temperature; (hx) A step of washing the third mixture with an aqueous solution of a polar solvent at a fifth temperature; (hxi) A process of repeating the cleaning process (hx); (hxii) A step of collecting tricaprylin crystals; and (hxiii) A process of evaporating the residual solvent from the crystals using a rotary evaporator. The method according to any one of claims 9 to 12, further comprising:

14. The method according to claim 9, wherein the concentrated acid contains sulfuric acid.

15. The method according to claim 10, wherein the first temperature is in the range of about 90°C to about 120°C.

16. The method according to claim 10, wherein the first specified time is approximately 3 hours to approximately 5 hours.

17. The method according to claim 11, wherein the second temperature is in the range of about 90°C to about 120°C.

18. The method according to claim 11, wherein the second specified time is in the range of approximately 15 hours to approximately 24 hours.

19. A pharmaceutical composition comprising the ultra-high purity composition described in claim 1.

20. A method for providing preventive or therapeutic treatment for a disease or disorder in a subject in need thereof, comprising the step of administering a composition containing ultra-high purity tricaprylin to the subject.

21. The disease or disorder is any one or more of the following: cranial trauma, stroke, hypoxia, myocardial infarction, refeeding syndrome, anorexia, epilepsy, neurodegenerative diseases such as dementia, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis, lipid metabolism disorders such as glucose transporter deficiency (GLUT1 deficiency), VL-FAOD, and mitochondrial diseases such as mitochondrial thiolase deficiency, Huntington's disease, cancer such as T-cell lymphoma, astrocytoma, and glioblastoma, HIV, rheumatic diseases such as rheumatoid arthritis, and gout, chronic inflammatory bowel disease, ulcerative colitis, Crohn's disease, lysosomal storage disorders, sphingolipidosis, Niemann-Pick disease, diabetes mellitus, migraine and migraine headache, epilepsy, infantile spasms, and any one or more of the effects or side effects of chemotherapy. The method according to claim 20.

22. The method according to claim 20, comprising the step of administering the ultra-high purity composition of tricaprylin described in claim 1 to a target.

23. The method according to claim 20, comprising the step of administering to a subject an ultra-high purity composition of tricaprylin prepared by the method of claim 7.

24. The method according to claim 20, wherein an ultra-high purity composition of tricaprylin is administered orally.

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