Mixed odd / even fatty acid triglycerides for cognitive health

Abstract

A fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, C11 fatty acids or mixtures thereof, and the even chain fatty acids are selected from C6, C8, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1.

Description

MIXED ODD / EVEN FATTY ACID TRIGLYCERIDES FOR COGNITIVE HEALTHFIELD OF THE INVENTION

[0001] The invention relates to compositions for the treatment of cognitive health issues. More particularly, the invention relates to mixed odd / even fatty acid triglycerides for the treatment of cognitive health issues, such as Alzheimer’s.BACKGROUND OF THE INVENTION

[0002] It is a sad fact of life that as individuals enter their 70’s and 80’s, they become increasingly vulnerable to cognitive health problems. These impairments can be evidenced in numerous ways, including well-known disabilities such as Alzheimer’s disease and drug-resistant epilepsy.

[0003] Alzheimer’s itself affects 6.9 million people 65 and older in the United States, with two-thirds of them being women. Fifty-five million are currently affected worldwide, and this is projected to rise to 140 million by 2050. This trend is also expected to continue in the U. S., particularly as demographics shift toward an older population.

[0004] Symptoms of Alzheimer’s are treated conventionally with cholinesterase inhibitors such as Donepezil (Aricept), Rivastigmine (Exelon) and galantamine (Reminyl), which slow the breakdown of acetylcholine (Ach), however, there is no cure. Work in this area is ongoing.

[0005] Even chain medium chain triglycerides (“MCTs”), i.e., fatty acids C6 through C12 have shown efficacy in the treatment of a number of cognitive health applications, mainly by supplying ketone bodies to the brain as a secondary energy source. These include targeting cognitive health and brain metabolite applications, such as Alzheimer’s disease, drug resistant epilepsy and pet cognitive health.

[0006] In particular, one area of study has focused on the so-called anaplerotic reactions, i.e., chemical reactions that form intermediates of a metabolic pathway such as the Krebs (TCA) cycle. Examples of such efforts are shown in the use of microbial anaplerotic oils, as shown in U. S.10,874,131, U. S. 11,457,655. and EP 3897185. These references disclose the use of oils from microbials which contain elevated amounts of odd chain fatty acids (“OCFAs”). These include physical mixtures of even chain fatty acids (“ECFAs”) and OCFAs, where the OCFA’s andECFA’s are long chain fatty acids between 13-22 carbons long. These references discourage the use of C5 and C7 OCFAs, specifically the triglycerides (“TAG’s”) tripentanoin and triheptanoin; instead favoring C15 and C17 OCFAs with other long chain (> C14) ECFAs.

[0007] In another study, Borges, Kaul, Germaine, Kaul, and O’Brien in Randomized trial of addon triheptanoin vs MCTs in adults with refractory epilepsy, Epilepsia Open, 2019, 4, 153-163, Borges, Kaul, Germaine. Kaul, and O'Brien, contrast the use of Cs / Cio fatty acids with triheptanoin (C7). However, the reference does not disclose the mixing of C7 fatty acids with / C10 fatty acids in a triglyceride.

[0008] Nevertheless, work has continued to develop compositions useful for the improvement of cognitive health. It has surprisingly been found that mixed odd / even fatty acids (“MOEFA”) MCTs demonstrate an ability to treat such conditions, such as Alzheimer’s.SUMMARY OF THE INVENTION

[0009] The subject matter of the present disclosure relates to mixed odd / even fatty acid triglycerides for the treatment of cognitive health issues, such as Alzheimer’s.

[0010] In one embodiment, the present disclosure provides a fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, C11 fatty acids or mixtures thereof, and the even chain fatty acids are selected from Ce, C8, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1.

[0011] In another embodiment, the present disclosure provides a process to produce a fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, Cn fatty acids or mixtures thereof, and the even chain fatty acids are selected from Ce, Cs, C10. C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4: 1, the process comprising esterification reactions, transesterification reactions, interesterification reactions or a combination thereof.

[0012] In still another embodiment, the present disclosure provides a composition comprising a fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, Cn fatty acids or mixtures thereof, and the even chainfatty acids are selected from C6, C8, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1, and components selected from pharmaceutically acceptable earners, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants, masking agents, coloring agents, flavoring agents, sweetening agents, therapeutic agents, prophylactic agents, or combinations thereof.

[0013] In an embodiment, the present disclosure provides a method comprising administering a fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, C11 fatty acids or mixtures thereof, and the even chain fatty acids are selected from C6, C8, C10, C12 fatty acids or mixtures thereof, and wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1, to an individual for the treatment of Alzheimer’s disease, epilepsy, and other syndromes and diseases associated with metabolic dysfunction in the brain which benefits from the use of a ketogenic diet to enhance brain metabolism.

[0014] In another embodiment, the present disclosure provides a method comprising administering a composition comprising a fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, C11 fatty acids or mixtures thereof, and the even chain fatty acids are selected from C6, C8, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1, and components selected from pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants, masking agents, coloring agents, flavoring agents, sweetening agents, therapeutic agents, prophylactic agents, or combinations thereof, to an individual for raising blood ketone levels.

[0015] In still another embodiment, the present disclosure provides a method comprising administering a fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, Cn fatty acids or mixtures thereof, and the even chain fatty acids are selected from C6, C8, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1, to an individual for raising blood ketone levels.

[0016] In an embodiment, the present disclosure provides a method comprising administering a fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, C11 fatty acids or mixtures thereof, and the even chain fatty acids are selected from C6, C8, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1 to animals for cognitive and other health related diseases associated with metabolic disfunction in the brain which benefits from the use of a ketogenic diet to enhance brain metabolism.

[0017] In another embodiment, the present disclosure provides a mixture of triglycerides comprising a fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, Cn fatty acids or mixtures thereof, and the even chain fatty acids are selected from C6, C8, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4: 1.

[0018] In an embodiment, the present disclosure provides a composition comprising a mixture of triglycerides, the mixture comprising a fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, Cn fatty acids or mixtures thereof, and the even chain fatty acids are selected from Ce, Cs, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1.

[0019] In still another embodiment, the present disclosure provides a fatty acid diglyceride comprising odd chain fatty acids and even chain fatty acids on the same glycerol backbone, wherein the odd chain fatty acids are selected from C7, C9, Cn fatty acids or mixtures thereof, and the even chain fatty acids are selected from C6, C8, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1. Such diglycerides can similarly be used in the treatment of cognitive health issues, such as Alzheimer’sBRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 illustrates the structure of MOEFA MCTs.

[0021] Figure 2 illustrates the formation of l,3-Dioxan-5-ol (Acetal).

[0022] Figure 3 illustrates the conversion of Acetal to MOEFA MCT.

[0023] Figure 4 the formation of MOEFA MCTs via the interesterification of OCFA and ECFA triglycerides.

[0024] Figure 5 illustrates the formation of MOEFA MCTs structured lipid via enzymatic transesterification of a single fatty acid triglyceride with an ester of another fatty acid.

[0025] Figure 6 illustrates the generalized formation of MOEFA MCT structured lipids via enzymatic processing.

[0026] Figure 7 illustrates the formation of MOEFA MCTs via esterification of glycerol with a mix of OCFAs and ECFAs.

[0027] Figure 8 illustrates comparison of restoring glutamate signaling using a C7 / C8 interesterified MOEFA MCT vs triheptanoin and trioctanoin.

[0028] Figure 9 illustrates improved learning index of Alzheimer’s model nematodes when fed C7 / C12 interesterified TAGs versus trioctanoin.

[0029] Figure 10 illustrates improved learning using Alzheimer’s model nematodes fed with C7 / C12 MOEFA MCTs vs a control and trioctanoin.

[0030] Figure 11 illustrates improved learning index for healthy wild type nematodes fed various MOEFA MCTs vs single fatty acid TAG and physical mixes of single fatty acid TAGs.

[0031] Figure 12 illustrates improved learning index for Alzheimer’s model nematodes fed various MOEFA MCTs vs single fatty acid TAG and physical mixes of single fatty acid TAGs.

[0032] Figure 13 illustrates that the improved performance of MOEFA MCTs holds for multiple fatty acid MCTs, not just two fatty acid systems.GLOSSARY OF ABBREVIATIONS

[0033] MCTs - medium chain triglycerides

[0034] TAG(s) - Triacylglycerides also known as triglycerides

[0035] OCFA(s) - odd chain fatty acid(s) - medium chain fatty acids with an odd number of carbons, specifically C7 (heptanoic (enanthic) acid; C9 (nonanoic (pelargonic) acid); C11 (undecanoic acid).

[0036] ECFA(s) - even chain fatty acid(s) - medium chain fatty acids with an even number of carbons, specifically C6 hexanoic (caproic) acid, C8 octanoic (caprylic) acid, C10 decanoic (capric) acid, C12 dodecanoic (lauric) acid).

[0037] MOEFA MCT - a triglyceride that contains both odd and even chain fatty acids on the same glycerol backbone.

[0038] C. elegans - the scientific name of the nematodes used to evaluate MCT oils in this application (Caenorhabdilis elegans).

[0039] C7 - When used in a data graph, this denotes triheptanoin, a triglyceride made exclusively with heptanoic acid.

[0040] C8 - When used in a data graph, this denotes trioctanoin, a triglyceride made exclusively with octanoic acid.

[0041] C7C8 IE (also designated as C7C8 IE 1:1) - a triglyceride consisting of a 1:1 weight ratio of C7 and Cs fatty acids, with a randomized positional distribution of the fatty acids. This weight ratio is equivalent to a 1.1:1 molar ratio of C7 and Cs fatty acids, respectively. (See Example 2)

[0042] C7C8 PM - a mixture of triheptanoin and trioctanoin consisting of a 1:1 weight ratio of C7 TAG and Cs TAG, with no randomized positional distribution of the fatty acids. This weight ratio is equivalent to a 1.1:1 molar ratio of C7 and Cs fatty acid equivalents in the respective TAGs comprised of a single fatty acid. This blend was used to generate C7C8 IE 1:1 (See Example 2)

[0043] C7C8 SL 1:2 - a structured lipid (SL) consisting of mostly C7 fatty acid at the sn-2 position of the glycerol backbone and mostly Cs fatty acid - at the sn- 1 and 3 positions. (See Example 3)

[0044] C7C12 IE 2:1 - a triglyceride consisting of a 2:1 molar ratio of C7 and C12 fatty acids, with a randomized positional distribution of the fatty acids. (See Example 2)

[0045] C7C12 PM - a mixture of triheptanoin and trilaurin consisting of a 2:1 molar ratio of C7 TAG and C12 TAGs, with no randomized positional distribution of the fatty acids. This blend was used to generate C7C12 IE 2:1 (See Example 2)

[0046] C7 / C12 IE 1:1 - a triglyceride consisting of a 1:1 weight ratio of C7 and C12 fatty acids, with a randomized positional distribution of the fatty acids. This weight ratio is equivalent to a 1.5:1 molar ratio of C7 and C12 fatty acids, respectively. (See Example 2)

[0047] C7C12 SL 2:1 - a structured lipid (SL) consisting of mostly C12 fatty acid at the sn-2 position of the glycerol backbone and mostly C7 fatty acid at the sn-1 and 3 positions. (See Example 3)

[0048] C7C8C9 IE - a triglyceride consisting of a 1.5: 1:1.5 molar ratio of C7, Cs and C9 fatty acids, respectively, with a randomized positional distribution of the fatty acids. (See Example 4)DETAILED DESCRIPTION OF THE INVENTION

[0049] In one embodiment, the present disclosure provides a fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, Cn fatty acids or mixtures thereof, and the even chain fatty acids are selected from Ce, Cs, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1.

[0050] The fatty acid triglycerides described in the present disclosure provide an alternative to the currently available MCTs by combining even chain and odd chain fatty acids on the same glycerol backbone, resulting in a more effective treatment for cognitive health applications. The resultant triglyceride containing mixed odd / even fatty acids is shown in Figure 1.Figure 1. Structure of a Mixed Odd / Even Fatty Acids MCT

[0051] The fatty acid triglycerides of the present subject matter contain medium chain triglycerides (MCT), i.e., (fatty acids C6 through C12) containing at least one fatty acid with a carbon chain length which is an odd number, specifically (C7 (heptanoic (enanthic) acid); C9 (nonanoic (pelargonic) acid); Cn (undecanoic acid), or combinations thereof, and at least one fatty acid with a carbon chain which is an even number, specifically (Ce (hexanoic (caproic) acid), C8 (octanoic (caprylic) acid), C10 (decanoic (capric) acid), C12 (dodecanoic (lauric) acid)) or combinations thereof, all on the same backbone. The positions of these fatty acids can be in any combination of the sites sn-1, 2 or 3 as shown in Figure 1. Thus, the fatty acid triglycerides contain mixed odd / even carbon number fatty acids on the same backbone, i.e., an MOEFA MCT. The MOEFA MCT can be present in a mixture with other inventive MOEFA MCTs as described,and / or with other triglycerides, such as even chain fatty acid triglycerides, odd chain fatty acid triglycerides, or as purified components that have been isolated / separated from the even chain and / or odd chain triglycerides.

[0052] The MOEFA MCTs can have any combination of even and odd fatty acid chains as long as the ECFA are C6, C8, C10 or C12 and the OCFA are C7, C9 or C11, and can include combinations of a single ECFA and a single OCFA, a single ECFA with two or more different OCFAs, or a single OCFA with two or more different ECFAs.

[0053] Preferably, the fatty acid triglyceride has a molar ratio of ECFA to OCFA from 1:3 to 3:1 More preferably, the molar ratio is 1:2 to 2:1. Even more preferably, the molar ratio is 1:1.2 to 1.2:1.

[0054] Preferably, in the fatty acid triglyceride, the odd chain fatty acid is C7, and the even chain fatty acid is C8 or C12. Even more preferably, the odd chain fatty acid is C7, and the even chain fatty acid is C8, or the odd chain fatty acid is C7 and the even chain fatty acid is C12.

[0055] Additives

[0056] Compositions containing the MOEFA MCTs of the present subject matter can also include additives selected from pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants, masking agents, coloring agents, flavoring agents, sweetening agents, therapeutic agents, prophylactic agents, or combinations thereof.

[0057] Without wishing to be bound by theory, the MOEFA MCTs of the present disclosure are believed to treat cognitive heath issues by augmenting energy transport to the brain, where ketone bodies are supplied to the brain as a secondary energy source. Even chain and odd chain fatty acids are metabolized differently so that the different metabolites enter the brain TCA cycle (Krebs cycle) at different parts of the cycle, so that with the MOEFA MCTs there is no swamping of a single metabolic pathway. The impact of this phenomenon translates to increased efficacy, resulting in lower dosing, and fewer side effects like gastrointestinal distress. The MOEFA MCTs have been found to better regulate glutamate and serotonin pathways than OCFA glycerides alone, ECFA glycerides alone or physical mixes of OCFA and ECFA glycerides with equivalent fatty acid distributions

[0058] MOEFA MCTs function by improving glutamate signaling and serotonin signaling. Glutamate signaling affects learning, memory, stress, happiness, and appetite. Glutamateexicitotoxicity can result in depression, Alzheimer’s, Parkinson’s, Huntington’s & ALS. Serotonin signaling is active in brain areas involved in learning and memory. Pharmacological and genetic manipulations of the serotonin receptor are known to modify memory performance in humans and rodents.

[0059] Serotonin signaling is active in brain areas involved in learning and memory, so that Pharmacological and genetic manipulations of the serotonin receptor are known to modify memory performance in humans and rodents. During Alzheimer's disease, serotonin signaling is thought to be reduced through loss of receptor expression. The MOEFA MCTs of the present disclosure are believed to improve the stimulation of serotonin signaling, so that, through improved serotonin signaling it may be possible to retrieve lost memory from Alzheimer’s disease.

[0060] The MOEFA MCTs of the present subject matter are believed to aid in the treatment of certain forms of epilepsy, since ketogenic diets have long been known in the treatment of epilepsy, and these compounds are believed to provide an excellent energy source for these diets.

[0061] The MOEFA MCTs of the present subject matter are also believed to be beneficial for the treatment of neurodegenerative diseases, by mitigating glutamate imbalance. Glutamate is the primary excitatory neurotransmitter, and 60% of the neurons in the brain utilize glutamate as their primary neurotransmitter. Excessive glutamate can over-stimulate its cellular receptors and thereby induce neurodegeneration, and contribute to the onset of Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis. Huntington’s disease, epilepsy, and schizophrenia.

[0062] The Examples below demonstrate the efficacy of the MOEFA MCTs of the present disclosure in applications such as Alzheimer’s disease, drug resistant epilepsy, especially GLUT1 epilepsy, Huntington’s disease, and any other cognitive health syndrome. In addition, there is no reason to believe that MOEFA TAGs cannot be used in other health applications currently served by traditional ECFA MCTs. The impact on metabolism of a synergistic effect of placing OCFAs and ECFAs on the glyceride backbone could have applications in general nutrition, energy delivery to infants and others with acute, temporary or chronic gastrointestinal issues, weight loss, Type II diabetes, energy drinks or any other general health application associated with metabolic syndrome disorders and / or currently served by traditional ECFA MCTs.

[0063] It is also believed that the present MOEFA MCTs could prove effective in SEDDS (Self Emulsifying Drug Delivery Systems), which are a combination of various components to formemulsions to carry hydrophobic drug actives into the blood stream. Oils play an important role in SEDDS, most importantly as a carrier for hydrophobic drug substances. These novel MOEFA MCTs can not only aid in the utility of SEDDS s, but after delivery of the drug substance they can go off on their own to effect positive metabolic activities for the patient.

[0064] Production of MOEFA MCTs

[0065] The MOEFA MCTs of the present subject matter can be produced by reactions converting glycerol to di-and triglycerides, or more specifically, structured lipids, esterification reactions, transesterification reactions, interesterification reactions or a combination thereof. Such reactions are shown in Figures 2 to 7. Preferably, the reactions are esterification reactions, transesterification reactions, interesterification reactions or a combination thereof. Preferably, the reactions are selected from uncatalyzed reactions, enzymatic reactions, base catalyzed reactions, acid catalyzed reactions or combinations thereof.

[0066] Preferably, the reactions utilize a feedstock selected from a carboxylic acid, an alkyl ester of a carboxylic acid, a carboxylic anhydride, or carboxylic derivatives.

[0067] Further, the reactions may utilize a step to reduce organochloro and glycidol species below 0.05 ppm in the glycerides, as shown in U. S. Patent No. 9,051,260.

[0068] Preferably, the carboxylic derivatives are selected from halides, carbonates, mixed anhydrides, or heteroatom derivatives.

[0069] As demonstrated in the Examples below, the invention shows an unexpected increase in performance in interesterified, odd / even FA chain length TAGs when compared to single FA TAGs or currently available MCTs comprising even chain length FAs, i.e., C7 / C8 TAGs (triacylglycerides) when compared to the performance of the C7 or Cs TAGs individually. More to the point, the physical blend of C7 and Cs TAGs does not perform as well as the interesterified C7 / C8 structured lipids. This enriched stream is then subjected to an enzymatic hydrolysis using a 1,3 specific lipase, cleaving the ester linkages at the 1 and 3 positions on the glycerol.

[0070] EXAMPLESThe following examples further detail and explain the inventive compositions of the present disclosure and demonstrate the efficacy of MOEFA MCTs for improved efficiency in treating cognitive health issues. Those skilled in the art will recognize many variations that are within the spirit of the invention and scope of the claims.

[0071] Protocols

[0072] In the following examples, the following protocols were utilized.

[0073] Nematode culture and strains

[0074] C. elegans nematode strains were maintained at 20°C on nematode growth medium (NGM) agar plates seeded with Escherichia coli strain OP50 according to standard protocol, unless indicated otherwise. For experiments, nematodes were synchronized to the LI stage by isolation of eggs from adult hermaphrodites through alkaline hypochlorite treatment and overnight hatching in M9-Tween medium.

[0075] Glutamate signaling assay

[0076] Wild-type and ZB 1106 nematodes with the genotype glt-3(bz34) IV; glt-l(ok206) X. were used.

[0077] Synchronized LI nematodes were grown on NGM plates with different concentrations of MCTs until young adult stage (grown for 72 h at 20°C). MCTs were dissolved in ethanol and added to the nematode food (OP50 E. coli) at 0.166% concentration. MCT-treated nematodes were compared to a vehicle control (0.5% ethanol). Wild type nematodes were also tested in the presence of the vehicle control (0.5% ethanol).

[0078] The number of reversal movements, which are increased in the ZB 1106 strain due to glutamate spillover, were quantified. Nematodes were analyzed by a touch to the head with an eyelash to induce a reversal movement. When the response to touch (the backward movement) was competed, the number of reversals were counted for the subsequent 90 seconds.

[0079] Alzheimer’s memory assay

[0080] Nematodes of strain CL2355 with the genotype smg-l(cc546)[pCL45(snb-l:: Abeta 1- 42::3’UTR (long) + mlt-2:: GEP] I. and strain CL2122 with genotype dvIsl5[(pPD30.38) unc- 54 vector) + (pCL26) mlt-2:: GFP] were used.

[0081] Synchronized LI nematodes were grown on NGM plates with different concentrations of MCTs until L4 stage (grown for 72 hours at 16°C). Next, nematodes were upshifted from 16° to 24°C for 24 hours to induce amyloid expression. MCTs were dissolved in ethanol and added to the nematode food (OP50 E. coli at the desired concentration. MCT-treated nematodes were compared to a vehicle control (0.5% ethanol).

[0082] Next, nematodes were washed off the plates and starved in M9 liquid medium with no food for one hour. Following the starvation period, the nematodes were placed on fresh NGM plateswith OP50 E. coli while in the presence of 10% butanone (dissolved in ethanol) for one hour. The butanone was spotted on the center of the lid of the plate. As a control, a naive population of nematodes were fed without the butanone odor. Chemotaxis assay plates were prepared by spotting 1 µl of 100% ethanol and 1 µl of 10% butanone on either side of a 9-cm plate.

[0083] For the chemotaxis assay, approximately 100 nematodes were placed at the side of the plate and nematodes were allowed to crawl for one hour before the number of nematodes were scored in each of the regions. The chemotaxis index was then calculated. The chemotaxis index is found by the (# of nematodes in the butanone region) - (# of nematodes in the ethanol region) divided by the total number of nematodes. The learning index was calculated by subtracting the chemotaxis index of trained nematodes from those of naive nematodes.

[0084] Serotonin production assay

[0085] The nematode strain GR1333 with genotype yzls 71 [tph-lp:: GEP + rol-6(sul006)] V. was used.

[0086] Synchronized LI nematodes were grown on NGM plates with different concentrations of MCTs. Well-fed-treated nematodes were grown for 96 hours at 20°C in the presence of OP50 E coli. Starvation-treated nematodes were grown for 72 hours at 20°C in the presence of OP50 E coli. and then transferred to NGM plates with no food for 24 hours. MCTs were dissolved in ethanol and added to the nematode food at the desired concentration. MCT-treated nematodes were compared to a vehicle control (0.5% ethanol).

[0087] Green fluorescent protein (GFP) levels were measured in the nematodes after 96 hours. For imaging, animals were mounted on 3% agarose pads and immobilized using 1 µl of 1mM sodium azide. Images were taken using an Olympus 1X71 inverted microscope with Olympus DP73 Camera, in the GFP channel (488 nm) at 10x magnification without binning, with exposure time of approximately 700 ms (same exposure during the entire experiment).

[0088] Background correction was performed on the images to calculate fluorescence intensity (i.e., corrected total fluorescence was calculated by subtracting the total fluorescence of the background from the total fluorescence of the nematode).Example 1

[0089] Reaction diagram (Figures 2 and 3)MOEFA MCT via highly refined Acetal intermediate

[0090] Glycerol (457.65 g, 4.97 mol) was heated to 45 °C and catalyst (p-toluenesulfonic acid, 5.90 g) was added under a nitrogen blanket at ambient pressure. Propionaldehyde (447.12 g, 7.70 mol, 1.55 equivs) was added in portions. The acetal formation reaction was exothermic, and additional rate was used to control the reaction temperature (reaction temperature range - 32-58 °C). Initially, there was a two-phase system, but the aldehyde dissolved into the glycerol phase. Upon completion of the propionaldehyde addition sodium carbonate (2.24 g suspended in 6.4 g water) was added. System pressure was reduced to facilitate the removal of excess propionaldehyde and water of reaction. The drying step temperature range was 56-102 °C and the overhead temperatures ranged from 42 -74 °C. Final system conditions were a pot temperature of 102 C, an overhead temperature of 74 °C at a pressure of 33 mm Hg. Once dried, the reaction mix (614.92 g, 84.2% yield) was taken forward to the reactive distillation step without further processing. The product contained 24.32 % of the trans 1,3-dioxane isomer, 42.43% of the two dioxolane isomers, 22.05% of the cis 1,3-dioxane isomer and 10.56% glycerol (balance - minor unidentified species).Acetal purification

[0091] The acetals (809.77g total charge) and catalyst (p-toluenesulfonic acid (7.60 g) add to a 500 mL round bottom flask, The acetals were distilled through a 280 mm distillation column (25 mm ID) fitted with a reflux splitter. During the distillation, the concentration of one of the 2-ethyl-l,3-dioxan-4-ol isomers was enriched (Acetal A). The pot contents were refilled with dried reaction mix as the distillation progressed. This first pass distillation was a reactive distillation, where the other dioxolane / dioxane isomers in the pot continued to rearrange to form the more volatile Acetal A dioxane isomer. The system conditions were 5 mm Hg; pot temperature range - 73 - 88 °C; overhead temperature range - 63 - 65 °C; reflux ratio was 45:1 to 60:1. A total of 684.55 grams were recovered. The overhead stream (97.8% Acetal A) was carried forward.Reaction diagram (Figure 2). Formation of High Purity l,3-dioxan-2-olAcetal heptanoate

[0092] Acetal A (20.20 g, 0.15 mol) and methyl heptanoate (51.57 g, 0.19 mol, 1.27 equiv) were combined in a 100 mL rb flask with an overhead recovery setup consisting of a condenser and a distillate receiver. The reaction mix was heated to 80 °C under a nitrogen atmosphere. Once the temperature had stabilized sodium methoxide (0.64 g, 25% in MeOH) was added in one portion. The reaction mix was then heated to 210 °C over 30 minutes. The progress of the reaction was monitored by intermittent sampling. After 6 hours the reaction was judged complete by the disappearance of the acetal peak in the GC scan. Acetal heptanoate was purified by recrystallization from THF / heptane (1 / 20; 10% loading).l,3-diacetyl-2-heptanoylglyceride

[0093] The acetal heptanoate (244.43 g, 1.00 mol) and acetic anhydride (552.87 g, 5.42 mol, 5.42 equiv) were combined and the clear solution was heated to 60 °C. Once the temperature stabilized p-toluenesulfonic acid (35.3 g) was added. The mix was stirred at 59-62 °C for 29 hours. The dark mix was taken up in heptane, neutralized with sodium bicarbonate then filtered. The heptane and excess acetic anhydride were stripped from the reaction mix under vacuum. Next, the 1,3-diacetyl-2-heptanylglyceride was recovered by distillation (pot temperature: 155-160 °C; overhead temperature: 118-120 °C; 1 mm Hg; purity > 99%).Heptanoic / octanoic structured triglyceride (Cv / CsSL 1:2)

[0094] l,3-diacetyl-2-heptanoylglyceride (1.75 g, 6.1 mmol), heptane (5.84 g) and methyl octanoate (7.14 g, 41.45 mmol, 3.4 equivs) were added and the clear solution was heated to 45 °C. Once the temperature stabilized Lipozyme RM (0.223 g) was added. The mix was stirred atambient pressure at 45 °C for 23.5 hours. After filtration, an oil was collected consisting of 17% trioctanoin and 77% CsCyCs structured lipid (SL).

[0095] Reaction Diagram (Figure 3). l,3-Dixoxan-2-ol to MOEFA MCT

[0096] This example shows the formation of a MOEFA MCT structured lipid comprising a triglyceride with predominantly C7 fatty acid equivalent at the sn-2 position and predominantly Cx fatty acid equivalents at the sn-l and 3 positions. The “s T stands for “stereospecifically numbered” to indicate a specific site on the glycerol backbone. Testing was performed with these samples according to the protocols listed in paragraphs

[0072] to

[0090] , The testing illustrated that the structured lipid showed significantly better performance in enhancing memory in wild type nematodes when compared to C7 and Cs TAGs as well as the C7 / C8 PM (physical mix) (Figure 11). This demonstrates the efficacy of MOEFA MCTs in cognitive health applications.Example 2

[0097] Reaction diagram (Figure 4).

[0098] Heptanoic / lauric interesterified triglyceride 2:1 molar ratio C?to C12 (C7 / C12IE 2:1)

[0099] Triheptanoin (82.47 g, 0.192 mol) and trilaurin (61.42 g, 0.0961 mol) were added and the clear solution was heated to 65 °C. Once the temperature stabilized, a portion of the solution (7.28 grams) was taken as a physical mix stream C7 / C12 PM 2: 1 (molar ratio). This physical mix stream would be used for comparison testing versus C7 / C12 interesterified and structured lipid TAGs. After the physical mix samples was taken, Lipozyme TL IM (3.21 g) was added. The mix was stirred at 65 °C for 20 hours. After filtration, an oil was collected consisting of triglycerides with ECN (equivalent carbon number - being defined as the sum of the number of carbons in the fatty acid chains of a TAG) of 21 (triheptanoin), 26 (diheptanoyl-dodecanoyltriglyceride), 31 (heptanoyl-didodecanoyltriglyceride) and 36 (trilaurin) with a distribution of 22:44:28:6, respectively (GC values uncorrected).Reaction Diagram (Figure 4). Generalized Interesterification of Two Single Fatty Acid Triglycerides

[0100] This example shows the formation of a MOEFA MCT interesterified triglycerides comprising of a triglyceride with a random distribution of C7 and C12 fatty acid equivalents (1:2 molar ratio of Cy / Cs). Testing was performed with these samples according to the protocols listed in paragraphs

[0072] to

[0090] , The interesterified MCTs in this oil showed significantly better performance in enhancing memory in Alzheimer model nematodes when compared to Cs TAGs (Figures 9 and 10) as well as C7 and Cs TAGs and the Cy / Cs PM (1:1 weight ratio physical mix)(Figure 12). Other interesterified MOEFA MCTs, such as this demonstrates the efficacy of MOEFA MCTs in cognitive health applications.

[0101] Using a similar methodology C7 / C8 IE 1:1 (mass ratio; 1.1:1 molar ratio C7 to Cs), C7 / C12 IE 1:1 (mass ratio; 1.5:1 molar ratio of C7 to C12), C7 / C8 PM was taken from the physical mix of C7 and C8 TAGs used to produce C7 / C8 IE 1:1.Example 3

[0102] Reaction diagram (Figure 5)

[0103] l,3-octanoyl-2-heptanoylglyceride structured lipid (Cv / Cs 1:2 SL (molar ratio 1:2 C7 to Cx fatty acids)) Transesterification to form a structured lipid

[0104] Triheptanoin (88.27 g, 0.21 mol) was combined with methyl octanoate (478.81 g, 3.03 mol, 3.87 equiv) and the clear solution was heated to 40 °C. Once the temperature stabilized Lipozyme RM (4.71 g) was added. The mix was stirred at 40 °C for 20 hours. The reaction mix was filtered, and methyl esters were removed under vacuum (pot temperature range: 103-151 °C; overhead temperature range: 98-103 °C; pressure 37-41 mm Hg, lowered to 1 mm Hg by the end of the strip). The methyl ester- stripped stream was then deodorized (184-186 °C; 7 mm Hg), treated with filter aid and then filtered. The resulting structured lipid contained (GC values, uncorrected): 2.8% triheptanoin, 28.5% C7C7C8 TAG; 64.7% C8C7C8 TAG and 0.9% trioctanoin. The sn-2 C7 fatty acid content was 96.5%. The designation sn-2 denotes the middle position on the glycerol backbone. The “ n” stands for “stereospecifically numbered” to indicate a specific site on the glycerol backbone.Reaction Diagram (Figure 5). Transesterification of Methyl Esters with a Single Fatty Acid Triglyceride

[0105] l,3-heptanoyl-2-dodecanoylglycerid structured lipid (C7 / C122:1 SL)

[0106] Trilaurin (100.93 g, 0.16 mol) was combined with methyl heptanoate (335.74 g, 2.33 mol, 14.7 equiv) and the clear solution was heated to 40 °C. Once the temperature stabilized Lipozyme RM (9.94 g) was added. The mix was stirred at 40 °C for 4.5 hours. The reaction mix was filtered, and methyl esters were removed under vacuum (pot temperature range: 95-180 °C; overhead temperature range: 83-146 °C; pressure 20-41 mm Hg, lowered to 1 mm Hg by the end of the strip). The methyl ester- stripped stream was then deodorized (184-186 °C; 7 mm Hg), treated with filter aid and then filtered. The resulting structured lipid contained (GC values, uncorrected): 8.6% diglycerides, 0.9% triheptanoin (ECN 21), 63.0% C7C12C7 TAGs (ECN 26); 25.1% C12C12C7 TAGs (ECN 31) and 2.4% trilaurin (ECN 36). The sn-2 C12 fatty acid content was 95.9%.

[0107] An alternate reaction pathway to a structured lipid is shown in Figure 6, as detailed below.Reaction Diagram (Figure 6). Alternate Route for Transesterification of Methyl Esters with a Single Fatty Acid Triglyceride

[0108] This example shows the formation of a MOEFA MCT structured lipid comprising a triglyceride with a specific distribution of C7 and Cs fatty acid equivalents (1:2 molar ratio of C7 / C8). Testing was performed with these samples according to the protocols listed in paragraphs

[0072] to

[0090] . The structured lipid MCTs in this oil showed significantly better performance in enhancing memory in Alzheimer model nematodes when compared to C7 and Cs TAGs as wellas the C7 / C8 PM (1.1:1 molar ratio physical mix) (Figure 11). This is also demonstrated in glutamate signaling trials (Figure 8). C7 / C12 2:1 IE MOEFA MCTs were shown to give better results than triheptanoin, trilaurin and a physical mix of those two triglycerides in trials with healthy wild type (Fig 11) and Alzheimer’s model nematodes (Figure 9). These examples demonstrate the efficacy of MOEFA MCTs in cognitive health applications.Example 4

[0109] Reaction diagram (Figure 7).C7 / C8 / C9 triglyceride from fatty acids esterificationC7 fatty acid (195.29 g, 1.50 moles, 1.32 equivalents), Cs fatty acid (144.40 g, 1.00 moles, 0.88 equivalents), C9 fatty acid (237.27 g, 1.50 moles, 1.32 equivalents), glycerol 104.98 g, 1.14 moles, USP grade), potassium carbonate (0.61 g in 3 g water) and activated carbon (3.94 g, Norit) were combined in a 1 L, 4 neck round bottom flask. The vessel was initially configured with a nitrogen inlet and a Dean-Stark trap with a condenser. The mix was heated slowly to 225 °C over 3.5 hours. The mix was held at 225 °C for 5 additional hours and then the system was cooled to ambient temperature to allow for a change in the overhead system configuration.

[0110] The excess fatty acids were stripped under vacuum over 3 hours. After an hour hold the reactor was cooled and vacuum broken with nitrogen. Upon cooling the product was filtered and analyzed. The undeodorized MCT was neutralized with sodium bicarbonate, dried and filtered and then the material was deodorized at 204 °C / 7 mmHg. A mix of TAGs from ECN (equivalent carbon number, the sum of the chain lengths of the fatty acids comprising the TAG) 21 to ECNThis example shows that esterification of fatty acids and glycerol is another way to produce MOEFA MCTs. Also, in this example, three fatty acids are used. Testing was performed with these samples according to the protocols listed in paragraphs

[0072] to

[0090] , This demonstrates that the improved learning effects observed are not limited to two fatty acid MOEFA systems. Figure 13 shows that this 3 fatty acid system works as well or better than the two-fatty acid MOEFA MCT to which it is compared.

Claims

We claim:

1. A fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, C11 fatty acids or mixtures thereof, and the even chain fatty acids are selected from Ce, Cs, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1.2 The fatty acid triglyceride of claim 1 wherein the molar ratio is from 1:3 to 3:1.3 The fatty acid triglyceride of claim 2 wherein the molar ratio is 1:2 to 2:1.The fatty acid triglyceride of claim 3 wherein the molar ratio is 1:1.2 to 1.2:1.5 The fatty acid triglyceride of claim 1 wherein the odd chain fatty acid is C7.6 The fatty acid triglyceride of claim 1 wherein the even chain fatty acid is C8 or C12.The fatty acid triglyceride of claim 1 wherein the odd chain fatty acid is C7, and the even chain fatty acid is C8 or C12.8 The fatty acid triglyceride of claim 7 wherein the even chain fatty acid is C8.9 The fatty acid triglyceride of claim 7 wherein the even chain fatty acid is C12.10 A process to produce the fatty acid triglyceride of claim 1 comprising esterification reactions, transesterification reactions, interesterification reactions or a combination thereof.11 The process of claim 10 wherein the reactions are selected from uncatalyzed reactions, enzymatic reactions, base catalyzed reactions, acid catalyzed reactions or combinations thereof.

12. The process of claim 10 further comprising a feedstock for the generation of triglycerides selected from a carboxylic acid, an alkyl ester of a carboxylic acid, a carboxylic anhydride, carboxylic derivatives or mixtures thereof.

13. The process of claim 12 wherein the carboxylic derivatives are selected from halides, carbonates, mixed anhydrides, or heteroatom derivatives.

14. A composition comprising the fatty acid triglyceride of claim 1 and components selected from pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants, masking agents, coloring agents, flavoring agents, sweetening agents, therapeutic agents, prophylactic agents, or combinations thereof.

15. A method comprising administering the fatty acid triglyceride of claim 1 to an individual for the treatment of Alzheimer’s disease, epilepsy, and other syndromes and diseases associated with metabolic dysfunction in the brain which benefits from the use of a ketogenic diet to enhance brain metabolism.

16. A method comprising administering the composition of claim 14 to an individual for raising blood ketone levels.

17. A method comprising administering the fatty acid triglyceride of claim 1 to an individual for raising blood ketone levels.

18. A method comprising administering the fatty acid triglyceride of claim 1 to animals for cognitive and other health related diseases associated with metabolic disfunction in the brain which benefits from the use of a ketogenic diet to enhance brain metabolism.

19. A mixture of triglycerides comprising a fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, C11 fatty acids or mixtures thereof, and the even chain fatty acids are selected from Ce, Cx, C10, C12 fattyacids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1.

20. A composition comprising a mixture of triglycerides, the mixture comprising a fatty acid triglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7, C9, C11 fatty acids or mixtures thereof, and the even chain fatty acids are selected from Ce, Cs, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1.1 A fatty acid diglyceride comprising odd chain fatty acids and even chain fatty acids, wherein the odd chain fatty acids are selected from C7. C9. C11 fatty acids or mixtures thereof, and the even chain fatty acids are selected from C6, C8, C10, C12 fatty acids or mixtures thereof, wherein the molar ratio of the odd chain fatty acids to the even chain fatty acids ranges from 1:4 to 4:1.

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