Dietary butyrate

Abstract

To provide a dietary source including butyrate with improved organoleptic properties for use in the prevention and / or treatment of cardiovascular disorders.SOLUTION: The present invention provides compounds having the formulae (1), (2), (3) and (4), or combinations thereof, for use in the treatment or prevention of cardiovascular disorders in a subject, where R1, R2, R3, R4, R5, and R6 independently represent a long chain fatty acid with 16 to 20 carbons.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a butyrate-containing food ingredient having improved organoleptic properties for use in the prevention and / or treatment of cardiovascular disorders. [Background technology]

[0002] Cardiovascular disorders account for about 20% of all annual deaths worldwide and remain the leading cause of death in both developed and developing countries (SK Wattanapitayakul et al., Pharmacology and Therapeutics, 89, 187-206 (2001)). Cardiovascular disorders are also the leading cause of disability later in life. Cardiovascular disorders affect the heart or blood vessels. The main cardiovascular disorder is atherosclerosis (also known as arteriosclerotic vascular disease), in which fatty patchy deposits (plaques or atherosclerotic plaques) develop in the walls of medium and large arteries, leading to reduced or blocked blood flow. Atherosclerosis is a form of arteriosclerosis (meaning hardening of the arteries). Arteriosclerosis interferes with the body's regulation of blood pressure and increases the risk of hypertension. The stiffening of the arteries prevents them from expanding to return blood pressure to normal. People with high blood pressure are at greater risk of stroke, heart attack, and kidney failure.

[0003] The main cause of atherosclerosis is still unknown. Atherosclerosis is a syndrome affecting arterial blood vessels that is a response to chronic inflammation in the arterial wall. It is mainly caused by the accumulation of macrophages and promoted by low-density lipoproteins (LDL, a plasma lipoprotein that carries cholesterol and triglycerides) without proper removal of fats and cholesterol from macrophages by functional high-density lipoproteins (HDL). Atherosclerosis is also commonly referred to as hardening or furring of the arteries. This condition is caused by the formation of multiple plaques in the arteries.

[0004] When atherosclerosis affects the arteries that supply blood to the heart (coronary artery disease), this can cause chest pain (angina) or, if an area of ​​heart muscle is destroyed, a heart attack (myocardial infarction). Reduction in oxygen-rich blood flow to the heart muscle can cause heart failure (a disorder in which the heart pumps blood insufficiently), which can lead to reduced blood flow, back-up of blood in the veins and lungs (congestion), and other changes that can further weaken the heart. Failure of the coronary circulation to provide an adequate circulatory supply to the heart muscle and surrounding tissues is called coronary heart disease.

[0005] Atherosclerosis affecting the arteries to the brain can lead to stroke, which occurs when an artery to the brain becomes blocked or ruptures, causing death of an area of ​​brain tissue (cerebral infarction).

[0006] In terms of mortality, the main cardiovascular disorders are stroke and heart attack, but cardiovascular disorders also encompass conditions such as aortic aneurysm and peripheral vascular disease, and are responsible for clinical conditions including renal vascular disease, vascular dementia and retinal disease. Prevention of cardiovascular disorders is not only about reducing mortality, but also about preventing disability and improving quality of life.

[0007] Initial treatment of cardiovascular disorders focuses on dietary and lifestyle interventions, such as increased exercise, eating a low-fat diet, and smoking cessation.

[0008] Numerous compounds have been proposed for the treatment or prevention of cardiovascular disorders, including salicylates (WO 2009 / 006583), statins (JK Liao, International Journal of Cardiology, 86, 5-18 (2002)), angiotensin-converting enzyme (ACE) inhibitors (US Pat. No. 5,684,016), angiotensin II receptor blockers (EP 1,604,664) and calcium channel blockers (EP 0,089,167).

[0009] Unfortunately, currently available treatments are not always fully satisfactory in terms of efficacy and / or in terms of the side effects that may be associated with the treatments.

[0010] It is known that many patients on statins remain at high risk for CVD. These patients have persistently elevated hsCRP despite significant reductions in LDL-C levels. This condition is defined as the so-called “residual inflammatory risk” and represents an interesting pharmacological target. Evidence for the relevance of this target comes from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) trial, which showed that direct reduction of inflammation with an IL-1β antagonist reduced the incidence of cardiovascular events, independent of LDL-C levels (PMRidker,N Engl J Med.2017 Sep 21;377(12):1119-1131). However, IL-1β antagonist treatment is cost-prohibitive and has important side effects.

[0011] It would therefore be highly desirable to have alternative compositions available for the treatment or prevention of cardiovascular disorders without the drawbacks described in the prior art.

[0012] Acetate, propionate, and butyrate in the human large intestine are the main short-chain fatty acids (SCFAs) produced by the microbiota after fermentation of resistant starch or dietary fiber. Once produced, SCFAs are absorbed into the intestinal enterocytes as an energy source, but some of these absorbed fatty acids reach the systemic circulation and regulate the biological activity of multiple biological systems and / or organs. There is evidence that SCFAs have anti-inflammatory effects and can reduce the development of various inflammatory diseases, including inflammatory bowel disease, colon cancer, and diabetes mellitus (PAGill, Aliment Pharmacol Ther. 2018 Jul; 48(1): 15-34).

[0013] However, the effects of SCFAs on atherosclerosis and subsequent cardiovascular disease remain poorly understood. Atherosclerosis is a general term describing any hardening (and loss of elasticity) of medium or large arteries due to atherosclerotic plaque formation within the arteries. Vascular researchers have previously demonstrated the role of inflammation in atherosclerosis. After atherosclerotic plaque formation is initiated, macrophages release proinflammatory cytokines that activate endothelial cells and recruit additional leukocytes. This recruitment leads to adhesion of leukocytes to endothelial cells, migration of leukocytes into the subendothelial space, and progression and maturation of the plaque. Within the plaque, inflammatory signals from activated leukocytes (especially IL1 and IL6) ultimately lead to plaque destabilization and rupture, as seen in myocardial infarction (PMRidker, Circ Res. 2016 Jan 8;118(1):145-56, PMRidker, Circ Res. 2019 Feb;124(3):437-450).

[0014] Recent clinical trial data now demonstrate that inflammation is a key driver of atherosclerosis, as previously suggested by epidemiological data. Circulating inflammatory biomarkers, including high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6), are associated with increased risk of cardiovascular events. This is independent of cholesterol and other traditional risk factors. In fact, randomized trials have shown that statin treatment, in addition to exhibiting a blood lipid-lowering effect (low-density lipoprotein cholesterol, known as LDL-C), also reduces hsCRP. Interestingly, the degree of reduction in hsCRP is proportional to the reduction in cardiovascular risk (PMRidker, J Am Coll Cardiol. 2016 Feb 16;67(6):712-723).

[0015] In vitro studies have demonstrated that after challenge, endothelial inflammatory responses are also reduced by SCFA pretreatment: endothelial cells pretreated with SCFA and challenged with LPS or TNF secrete less interleukin-6, express less vascular cell adhesion protein 1 (VCAM1), and have reduced leukocyte adhesion (M. Li, Front Pharmacol. 2018 May 23;9:533).

[0016] Other studies have confirmed that butyrate, but not acetate or propionate, significantly reduces cholesterol crystal-induced Nrlp3 inflammasome formation and activation in cultured endothelial cells.Furthermore, in vivo studies have demonstrated that butyrate has a protective effect on the arterial wall in a rodent model of carotid artery injury, which is associated with insufficient Nrlp3 inflammasome complex formation and activation (X. Yuan, Redox Biol.2018 Jun;16:21~31).

[0017] These in vitro and in vivo studies support the anti-inflammatory role of SCFAs and make butyrate a candidate for the prevention and / or treatment of atherosclerosis.

[0018] Common sources of butyrate are butyric acid and tributyrin, which is a triglyceride composed of three ester functional groups with three butyrate moieties and a glycerol backbone. Both butyric acid and tributyrin are generally regarded as safe (GRAS) food additives (21CFR582.60 and 21CFR184.1903, respectively) and are natural components of many dairy products. Butyric acid, however, is associated with negative organoleptic qualities, such as vomit, feces, and cheese-like odor characteristics. Tributyrin also has negative organoleptic qualities, especially a high degree of bitterness. These unpleasant taste and odor characteristics can make oral administration of compositions containing these compounds particularly difficult. The butyrate component of dairy products cannot be enriched, which requires the ingestion of significant amounts of dairy fat, which is not feasible for practical and nutritional reasons, especially since it would result in the ingestion of large amounts of unnecessary calories derived from animal fats.

[0019] Butyrate may be beneficial in the prevention and / or treatment of atherosclerosis, but currently there are no methods to deliver butyrate in a form that has acceptable organoleptic properties.

[0020] It would therefore be beneficial to provide a food-grade butyrate source with improved organoleptic properties compared to available solutions used in the treatment or prevention of cardiovascular disorders. Summary of the Invention

[0021] The present invention provides a compound that is a source of butyrate with improved sensory properties for use in the prevention or treatment of cardiovascular disease, and the compound has improved odor and / or taste compared to butyric acid, butyrate salts, and / or tributyrin.The compound can be used as a food source of butyric acid.The compound can be used, for example, in nutritional compositions, dietary supplements, beverages, and pet care products.

[0022] The compounds and compositions can be used to prevent or treat cardiovascular disorders, particularly atherosclerosis, through reducing residual inflammatory risk. Cardiovascular disorders can be selected from the group consisting of atherosclerosis, coronary heart disease, myocardial infarction, angina pectoris, stroke, and / or heart failure. As mentioned above, stroke and myocardial infarction (heart attack) are the leading cardiovascular disorders in terms of mortality. Coronary heart disease and heart failure are also significant causes of death and debilitating ill health. Atherosclerosis is the underlying cause of many other cardiovascular disorders. Many people live with periodic attacks of hypertension and angina pectoris, which often negatively affect their quality of life and people are constantly concerned that such attacks may be a precursor to stroke, heart failure, or heart attack. Therefore, it would be advantageous to treat or prevent atherosclerosis, coronary heart disease, myocardial infarction, angina pectoris, stroke, and / or heart failure.

[0023] According to a first aspect of the present invention there is provided a compound having the formula:

[0024] [ka] [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently long-chain fatty acids having 16 to 20 carbons.

[0025] According to another aspect of the present invention, there is provided a composition comprising a compound having formula (1), (2), (3) or (4), or a combination thereof, for use in the prevention or treatment of a cardiovascular disorder in a subject. 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently long-chain fatty acids having 16 to 20 carbons.

[0026] In one embodiment, the composition comprises a compound having formula (1), a compound having formula (2), a compound having formula (3), and a compound having formula (4).

[0027] The composition can include a compound having formula (1) and a compound having formula (2).

[0028] The composition can include a compound having formula (1) and a compound having formula (3).

[0029] The composition can include a compound having formula (1) and a compound having formula (4).

[0030] The composition may include a compound having formula (2) and a compound having formula (3).

[0031] The composition can include a compound having formula (2) and a compound having formula (4).

[0032] The composition can include a compound having formula (3) and a compound having formula (4).

[0033] The composition can include a compound having formula (1), a compound having formula (2), and a compound having formula (3).

[0034] The composition can include a compound having formula (1), a compound having formula (2), and a compound having formula (4).

[0035] The composition can include a compound having formula (1), a compound having formula (3), and a compound having formula (4).

[0036] The composition can include a compound having formula (2), a compound having formula (3), and a compound having formula (4).

[0037] The composition can include a compound having formula (1), a compound having formula (2), a compound having formula (3), and a compound having formula (4).

[0038] In one embodiment, the compound having the formula (1), the compound having (2), the compound having (3) and the compound having (4) comprise at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% by weight of the total triglycerides of the composition.

[0039] In one embodiment, the compound having formula (1), the compound having formula (2), the compound having formula (3) and the compound having formula (4) constitute at least 50%, 60%, 70%, 80%, 90%, 95% or 99% by weight of the total butyrate moiety-containing triglycerides in the composition.

[0040] In one embodiment, tributyrin constitutes less than 10% by weight of the total triglycerides in the composition, preferably less than 8% by weight, more preferably less than 5% by weight of the total triglycerides in the composition.

[0041] In one embodiment, the composition further comprises dietary fiber and / or probiotics.

[0042] The compositions of the present invention may be in the form of nutritional compositions, for example foods, beverages, pet care products.

[0043] The compositions of the present invention may be in the form of a dietary supplement.

[0044] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , and / or R 6 is an unsaturated fatty acid, preferably a monounsaturated fatty acid.

[0045] In one embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , and / or R 6is selected from the group consisting of oleic acid, palmitic acid, or linoleic acid, preferably R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 Each of these is oleic acid.

[0046] The compounds and compositions of the invention may be useful in the prevention or treatment of cardiovascular disorders.

[0047] The compounds and compositions of the present invention may be useful in preventing the development and / or progression of cardiovascular disorders, particularly atherosclerosis, and atherosclerosis-related disorders, by reducing the residual inflammatory risk.

[0048] In one embodiment, the compounds or combinations thereof have improved organoleptic properties compared to butyric acid, tributyrin and / or butyrate salts.

[0049] In one embodiment, the compound is provided to a mammal, preferably a human, a pet, or a livestock animal. [Brief description of the drawings]

[0050] [Figure 1] Figure 1 shows the release of fatty acids from emulsions containing 200 mg of (A) tributyrin, (B) high oleic sunflower oil, and (C) a mixture of butyrate moieties-containing triacylglycerols (TAGs) according to the present invention, which have been digested either i) in simulated intestinal fluid (SIF), or (ii) sequentially in gastric fluid (SGF) followed by simulated intestinal fluid (SIF). [Diagram 2] FIG. 1 shows the overall extent of lipid digestion for a mixture of tributyrin, high oleic sunflower oil, and butyrate moiety-containing TAG according to the present invention, after both SIF and SGF-SIF. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] As used herein, the terms "comprising," "comprises," and "comprised of" are synonymous with "including" or "includes" or "containing" or "contains" and are inclusive, i.e., open-ended, and do not exclude additional, unrecited components, elements, or steps. The terms "comprising," "comprises," and "comprised of" also include the term "consisting of."

[0052] Triglycerides Triglycerides (also called triacylglycerols) are triesters derived from glycerol and three fatty acids. Under hydrolysis conditions, such as those during digestion, triglycerides can be a source of fatty acids. For example, tributyrin can be a source of 3 moles of butyric acid per mole of tributyrin.

[0053] Fatty acids are carboxylic acids with a long tail (chain). Fatty acids can be either unsaturated or saturated. Fatty acids that are not bound to other molecules are called free fatty acids (FFAs).

[0054] The term "fatty acid moiety" refers to the portion of a triglyceride that is derived from a fatty acid in an esterification reaction with glycerol. The triglycerides used in the present invention contain at least one butyric acid moiety and at least one long chain fatty acid moiety.

[0055] Preferred long chain fatty acids for use in the present invention are fatty acids having 16-20 carbon atoms. Examples of long chain fatty acids include oleic acid, palmitic acid, stearic acid, and linoleic acid. Preferably, the long chain fatty acid is oleic acid. For example, the present invention provides a compound having the formula:

[0056] [ka]

[0057] Other examples of triglycerides that can be used in the present invention include 1,3-dibutyryl-2-linoleoylglycerol, 1,3-dibutyryl-2-stearoylglycerol, 1-butyryl-2-oleoyl-3-palmitoylglycerol, 1-palmitoyl-2-oleoyl-3-butyrylglycerol, 1-butyryl-2-oleoyl-3-linoleoylglycerol, 1-linoleoyl-2-oleoyl-3-butyrylglycerol, 1-oleoyl-2-butyryl-3-linoleoylglycerol, 1-linoleoyl-2-butyryl-3-oleoylglycerol, 1-butyryl-2-linoleoyl- 3-oleoylglycerol, 1-oleoyl-2-linoleoyl-3-butyrylglycerol, 1-butyryl-2-stearoyl-3-oleoylglycerol, 1-oleoyl-2-stearoyl-3-butyrylglycerol, 1-butyryl-2-oleoyl-3-stearoylglycerol, 1-stearoyl-2-oleoyl-3-butyrylglycerol, 1,2-dioleoyl-3-palmitoylglycerol, 1-palmitoyl-2,3-dioleoylglycerol, 1,2-dioleoyl-3-linoleoylglycerol, and 1-linoleoyl-2,3-dioleoylglycerol.

[0058] The triglycerides of the present invention can be synthesized, for example, by the esterification reaction of long chain fatty acids and butyric acid with glycerol.

[0059] The triglycerides of the present invention can be synthesized, for example, by transesterification between tributyrin and another triglyceride containing long chain fatty acids. In one embodiment, high oleic sunflower oil is the source of long chain fatty acids. This creates a triglyceride that contains mainly butyrate and oleate moieties. This compound is dairy-free, cholesterol-free, and animal-derived-free. The fatty acids are released from the triglyceride by naturally occurring lipases in the gastrointestinal tract. Compared to butyrate salts, this compound does not add additional mineral salts to the final formulation.

[0060] Alternative methods for the synthesis of triglycerides can be determined by those skilled in the art as part of routine procedures. As an example, a method for obtaining 1,3-dibutyryl-2-palmitoylglycerol (BPB) is shown below.

[0061] [ka]

[0062] A single butyrate moiety-containing triglyceride can be used herein, or a mixture of different butyrate moiety-containing triglycerides can be used.

[0063] composition The compounds of the present invention can be administered in the form of a composition. Thus, the present invention provides a composition comprising a butyrate moiety-containing triglyceride as referred to herein for use in the prevention or treatment of a cardiovascular disorder in a subject.

[0064] In one embodiment, a combination of a compound having formula (1) and a compound having formula (2) is present in the composition defined herein.

[0065] In one embodiment, the compound having formula (1) is present in an amount of at least 10% by weight of the total amount of triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 10% by weight of the total amount of triglycerides in the composition.

[0066] In one embodiment, the compound having formula (1) is present in an amount of at least 15% by weight of the total amount of triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 15% by weight of the total amount of triglycerides in the composition.

[0067] In one embodiment, the compound having formula (1) is present in an amount of at least 20% by weight of the total amount of triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 20% by weight of the total amount of triglycerides in the composition.

[0068] In one embodiment, the compound having formula (1) is present in an amount of at least 20% by weight of the total amount of triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 30% by weight of the total amount of triglycerides in the composition.

[0069] In one embodiment, the compound having formula (1) constitutes about 20% to about 40% by weight of the total amount of triglycerides in the composition, and / or the compound having formula (2) constitutes about 30% to about 40% by weight of the total amount of triglycerides in the composition.

[0070] In one embodiment, the compound having formula (1) and the compound having formula (2) constitute at least 20%, 30%, 40%, 50%, 60%, or 70% by weight of the total triglycerides in the composition, preferably from about 40% to about 80% by weight, or from about 50% to about 75% by weight of the total triglycerides in the composition.

[0071] In one embodiment, the composition further comprises a compound having formula (3), preferably wherein the compound having formula (3) constitutes at least 2%, 3%, 4%, or 5% by weight of the total amount of triglycerides in the composition, and / or the composition further comprises a compound having formula (4), preferably wherein the compound having formula (4) constitutes at least 1%, 2%, or 3% by weight of the total amount of triglycerides in the composition.

[0072] In one embodiment, the compound having formula (1) is present in an amount of at least 20% by weight of the total amount of butyric acid-containing triglycerides in the composition, and the compound having formula (2) is present in an amount of at least 30% by weight of the total amount of butyric acid-containing triglycerides in the composition.

[0073] In one embodiment, the compound having formula (1) constitutes about 30% to about 50% by weight of the total amount of butyric acid-containing triglycerides in the composition, and / or the compound having formula (2) constitutes about 40% to about 60% by weight of the total amount of butyric acid-containing triglycerides in the composition.

[0074] In one embodiment, the compound having formula (1) and the compound having formula (2) constitute at least 20%, 30%, 40%, 50%, 60%, 70%, or 80% by weight of the total amount of butyric acid-containing triglycerides in the composition, and preferably constitute from about 60% to about 90% by weight of the total amount of butyric acid-containing triglycerides in the composition.

[0075] In one embodiment, the compound having formula (5) comprises at least 10% by weight of the total triglycerides in the composition, and / or the compound having formula (6) comprises at least 10% by weight of the total triglycerides in the composition.

[0076] In one embodiment, the compounds having formula (5) comprise at least 15% by weight of the total triglycerides in the composition, and / or the compounds having formula (6) comprise at least 15% by weight of the total triglycerides in the composition.

[0077] In one embodiment, the compounds having formula (5) comprise at least 15% by weight of the total triglycerides in the composition, and / or the compounds having formula (6) comprise at least 20% by weight of the total triglycerides in the composition.

[0078] In one embodiment, the compounds having formula (5) comprise at least 20% by weight of the total triglycerides in the composition, and / or the compounds having formula (6) comprise at least 20% by weight of the total triglycerides in the composition.

[0079] In one embodiment, the compound having formula (5) constitutes about 15% to about 30% by weight of the total amount of triglycerides in the composition, and / or the compound having formula (6) constitutes about 20% to about 30% by weight of the total amount of triglycerides in the composition.

[0080] In one embodiment, the compound having formula (5) and the compound having formula (6) constitute at least 20%, 30%, or 40% by weight of the total triglycerides in the composition, preferably from about 30% to about 60% by weight, or from about 40% to about 50% by weight of the total triglycerides in the composition.

[0081] In one embodiment, the composition further comprises a compound having formula (7), preferably wherein the compound having formula (7) constitutes at least 2% or 3% by weight of the total amount of triglycerides in the composition, and / or the composition further comprises a compound having formula (8), preferably wherein the compound having formula (8) constitutes at least 2% or 3% by weight of the total amount of triglycerides in the composition.

[0082] In one embodiment, the compound having formula (5) comprises at least 10% by weight of the total amount of butyrate-containing triglycerides in the composition, and the compound having formula (6) comprises at least 10% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0083] In one embodiment, the compound having formula (5) comprises at least 15% by weight of the total amount of butyrate-containing triglycerides in the composition, and the compound having formula (6) comprises at least 15% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0084] In one embodiment, the compound having formula (5) comprises at least 15% by weight of the total amount of butyrate-containing triglycerides in the composition, and the compound having formula (6) comprises at least 20% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0085] In one embodiment, the compound having formula (5) comprises at least 20% by weight of the total amount of butyrate-containing triglycerides in the composition, and the compound having formula (6) comprises at least 20% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0086] In one embodiment, the compound having formula (5) comprises from about 15% to about 30% by weight of the total amount of butyrate-containing triglycerides in the composition, and the compound having formula (6) comprises from about 20% to about 30% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0087] In one embodiment, the composition further comprises a compound having formula (7), preferably the compound having formula (7) comprises at least 2% or 3% by weight of the total amount of butyrate moiety-containing triglycerides in the composition, and / or the composition further comprises a compound having formula (8), preferably the compound having formula (8) comprises at least 2% or 3% by weight of the total amount of butyrate moiety-containing triglycerides in the composition.

[0088] In one embodiment, the composition of the present invention comprises 1,3-dibutyryl-2-linoleoylglycerol, 1,3-dibutyryl-2-stearoylglycerol, 1-butyryl-2-oleoyl-3-palmitoylglycerol, 1-palmitoyl-2-oleoyl-3-butyrylglycerol, 1-butyryl-2-oleoyl-3-linoleoylglycerol, 1-linoleoyl-2-oleoyl-3-butyrylglycerol, 1-oleoyl-2-butyryl-3-linoleoylglycerol, 1-linoleoyl-2-butyryl-3-oleoylglycerol, 1-butyryl-2-linoleoyl-3- ... glycerol, 1-oleoyl-2-linoleoyl-3-butyrylglycerol, 1-butyryl-2-stearoyl-3-oleoylglycerol, 1-oleoyl-2-stearoyl-3-butyrylglycerol, 1-butyryl-2-oleoyl-3-stearoylglycerol, 1-stearoyl-2-oleoyl-3-butyrylglycerol, 1,2-dioleoyl-3-palmitoylglycerol, 1-palmitoyl-2,3-dioleoylglycerol, 1,2-dioleoyl-3-linoleoylglycerol, and / or 1-linoleoyl-2,3-dioleoylglycerol.

[0089] In one embodiment, tributyrin comprises less than 10% by weight of the total amount of butyrate-containing triglycerides in the composition, preferably less than 8% by weight, more preferably less than 5% by weight of the total amount of butyrate-containing triglycerides in the composition.

[0090] Compositions of the present invention may be, for example, in solid (eg, powder), liquid, or gelatinous form.

[0091] The compositions of the present invention may be, for example, tablets, dragees, capsules, gelcaps, powders, granules, solutions, emulsions, suspensions, coated particles, spray-dried particles, or pills.

[0092] The composition may be in the form of a pharmaceutical composition and may include one or more suitable pharma- ceutically acceptable carriers, diluents, and / or excipients. Examples of such excipients suitable for the compositions described herein can be found in "Handbook of Pharmaceutical Excipients", 2nd Edition, (1994), (A Wade and PJ Weller, eds.). Acceptable carriers or diluents for therapeutic use are also well known in the pharmaceutical arts and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro, ed. 1985).

[0093] The pharmaceutical composition may comprise any suitable binder, lubricant, suspending agent, coating agent, and / or solubilizing agent as, or in addition to, the carrier, excipient, or diluent. Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, fluid lactose, β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc.

[0094] Preservatives, stabilizers, dyes, and even flavorings may be included in the composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents can also be used.

[0095] The composition may be a nutritional composition.

[0096] The expression "nutritional composition" refers to a composition that provides nutrition to a subject. This nutritional composition is preferably taken orally and may comprise a lipid or fat source and a protein source. Such a composition may also contain a carbohydrate source. In one embodiment, the nutritional composition contains only a lipid or fat source. In other specific embodiments, the nutritional composition contains a lipid (or fat) source together with a protein source, a carbohydrate source, or both.

[0097] In some particular embodiments, the nutritional composition according to the invention is an "enteral nutritional composition", i.e. a foodstuff in which administration of the composition involves the gastrointestinal tract. Introduction to the stomach may involve the use of a tube passing through the oral / nasal passages or an abdominal tube leading directly to the stomach. Such a tube may be used, particularly in a hospital or clinic.

[0098] In some particular embodiments, the composition is an oral nutritional supplement (ONS), a complete nutritional formula, a medicine, a medical product, or a food product. In some particular embodiments, the composition is administered to an individual as a drink. The composition may be stored as a powder in a sachet and then suspended in a liquid such as water when used.

[0099] The composition according to the invention may be a dietary supplement.

[0100] The term "dietary supplement" can be used to supplement the nutrition of an individual (typically used for nutritional supplementation, but also can be added to any type of composition intended for ingestion). It can be in the form of, for example, a tablet, capsule, lozenge, or liquid. Dietary supplements can further contain protective hydrocolloids (gums, proteins, modified starches, etc.), binders, film-forming agents, encapsulating agents / materials, wall / shell materials, matrix compounds, coatings, emulsifiers, surfactants, solubilizers (oils, fats, waxes, lecithin, etc.), adsorbents, carriers, fillers, co-compounds, dispersants, wetting agents, processing aids (solvents), flow agents, taste masking agents, bulking agents, gelling agents, and gel-forming agents. Dietary supplements may also contain conventional pharmaceutical additives and adjuvants, excipients, and diluents, including, but not limited to, water, gelatin of any origin, vegetable gums, lignin sulfonates, talc, sugar, starch, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifiers, buffers, lubricants, coloring agents, wetting agents, fillers, and the like.

[0101] When the composition is a nutritional supplement, it can be provided in a unit dosage form.

[0102] The composition according to the present invention may be a dairy product, a liquid beverage, a beverage powder, a dry soup, a dietary supplement, a meal replacement, a nutritional bar, a cereal, a confectionery product, or a dry pet food.

[0103] The composition may further comprise dietary fiber. "Dietary fiber" may comprise at least one indigestible oligosaccharide (e.g., prebiotic). The prebiotic may be present in an amount of 0.3-10% by weight of the composition. Dietary fiber and / or prebiotics may promote the production of endogenous butyrate by the intestinal flora, thus providing additional beneficial effects.

[0104] Prebiotics are usually indigestible in the sense that they are not broken down or absorbed in the stomach or small intestine. Thus, they remain intact when they enter the large intestine, where they are selectively fermented by beneficial bacteria. Examples of prebiotics include certain oligosaccharides, such as fructooligosaccharides (FOS), inulin, xylooligosaccharides (XOS), polydextrose, or any mixture thereof. In certain embodiments, the prebiotic may be fructooligosaccharides and / or inulin. In certain embodiments, the prebiotic is a combination of FOS and inulin, such as in the product sold by BENEO-Orafti under the trade name Orafti® Oligofructose (previously Raftilose®) or in the product sold by BENEO-Orafti under the trade name Orafti® Inulin (previously Raftiline®). Another example is a combination of 70% short chain fructooligosaccharides and 30% inulin, which is registered by Nestle under the trade name "Prebio 1". The nutritional composition of the present invention may also contain at least one milk oligosaccharide, which may be BMO (bovine milk oligosaccharides) and / or HMO (human milk oligosaccharides).

[0105] The composition of the present invention may further comprise at least one probiotic, such as a probiotic strain (i.e., a probiotic strain). Ingestion of a probiotic strain may also promote the production of endogenous butyrate by the intestinal flora, thus providing additional beneficial effects.

[0106] The most commonly used probiotic microorganisms are bacteria and yeasts, mainly of the following genera: Lactobacillus spp., Streptococcus spp., Enterococcus spp., Bifidobacterium spp. and Saccharomyces spp.

[0107] In some particular embodiments, the probiotic is a probiotic strain, hi some particular embodiments, the probiotic strain is a Bifidobacterium and / or a Lactobacillus.

[0108] The nutritional composition according to the invention may contain, on a dry weight basis, from 10e3 to 10e12 cfu of the probiotic strain per gram of composition, more preferably from 10e7 to 10e12 cfu, for example from 10e8 to 10e10 cfu of the probiotic strain.

[0109] In one embodiment, the probiotics are live bacteria. In another embodiment, the probiotics are non-replicating or inactivated. The probiotics may also be parts of the probiotics, such as cell wall components, or metabolic products of the probiotics. In some other embodiments, both viable and inactivated probiotics may be present. The nutritional composition of the present invention may further comprise at least one phage (bacteriophage) or a mixture of phages, preferably against pathogenic Streptococci, Haemophilus, Moraxella, and Staphylococci.

[0110] The nutritional compositions of the present invention generally contain a protein source, a carbohydrate source, and a lipid source. However, in some embodiments, especially when the nutritional composition of the present invention is a nutritional supplement or fortifier, only lipid (or a lipid source) may be present.

[0111] The nutritional composition according to the invention may contain a protein source. For example, in addition to soy-based protein sources, protein sources based on whey, casein, and mixtures thereof may be used. In terms of whey protein, the protein source may be based on acid whey or sweet whey or mixtures thereof and may contain α-lactalbumin and β-lactoglobulin in any desired ratio. In some embodiments, the main protein source is whey (i.e., more than 50%, such as more than 60% or more than 70% of the protein is derived from whey protein). The protein may be an intact protein or a hydrolyzed protein, or a mixture of intact and hydrolyzed proteins. In some embodiments, the protein source may also be partially or completely provided by the method of adding amino acids.

[0112] The term "intact" means that a major portion of the protein is intact, i.e. that the molecular structure is unchanged, e.g. at least 80% of the protein is unchanged, e.g. at least 85% of the protein is unchanged, preferably at least 90% of the protein is unchanged, even more preferably at least 95% of the protein is unchanged, e.g. at least 98% of the protein is unchanged. In a particular embodiment, the protein is completely unchanged.

[0113] The term "hydrolyzed" in the context of the present invention means that a protein has been hydrolyzed or broken down into its constituent amino acids.

[0114] Proteins can be either fully hydrolyzed or partially hydrolyzed. If hydrolyzed protein is required, the hydrolysis process can be carried out as desired as known in the art. For example, whey protein hydrolysates can be prepared by enzymatically hydrolyzing whey fractions in one or more steps. It has been found that if the whey fraction used as starting material is substantially lactose-free, the protein undergoes significantly less lysine blackage during the hydrolysis process. This can reduce the degree of lysine blackage from about 15% by weight of total lysine to less than about 10% by weight of total lysine, for example about 7% by weight of lysine, which significantly improves the nutritional value of the protein source.

[0115] In a particular embodiment, the proteins of the composition are hydrolyzed, extensively hydrolyzed or partially hydrolyzed. The degree of hydrolysis (DH) of the proteins may be between 2 and 20, or between 8 and 40, or between 20 and 60, or between 20 and 80, or greater than 10, greater than 20, greater than 40, greater than 60, greater than 80, or greater than 90. For example, nutritional compositions containing hydrolysates having a degree of hydrolysis of less than about 15% are commercially available from Nestle under the trade name Peptamen®.

[0116] In some embodiments, the protein is extensively hydrolyzed.

[0117] At least 70%, 80%, 85%, 90%, 95%, or 97% of the protein may be hydrolysed, hi certain embodiments, 100% of the protein is hydrolysed.

[0118] In one particular embodiment, the protein is provided as amino acids.

[0119] In one particular embodiment, the protein of the composition is a plant-based protein.

[0120] The nutritional composition according to the present invention may contain a carbohydrate source. Any carbohydrate source conventionally included in nutritional compositions may be used, such as lactose, sucrose, saccharose, maltodextrin, starch, and mixtures thereof.

[0121] The nutritional composition of the present invention may also contain all vitamins and minerals that are understood to be essential and nutritionally significant amounts essential in daily diet.Minimum requirements for certain vitamins and minerals have been established.Examples of minerals, vitamins and other nutrients that are optionally present in the composition of the present invention include vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B12, vitamin E, vitamin K, vitamin C, vitamin D, folic acid, inositol, niacin, biotin, pantothenic acid, choline, calcium, phosphorus, iodine, iron, magnesium, copper, zinc, manganese, chlorine, potassium, sodium, selenium, chromium, molybdenum, taurine and L-carnitine.Minerals are usually added in salt form.The presence and amount of certain minerals and other vitamins vary depending on the target population.

[0122] If necessary, the nutritional composition of the present invention may contain emulsifiers and stabilizers, such as soybean, lecithin, citrate esters of mono- and diglycerides, etc. The nutritional composition of the present invention may also contain other substances that may have beneficial effects, such as lactoferrin, osteopontin, TGFβ, slgA, glutamine, nucleotides, nucleosides, etc.

[0123] The nutritional composition according to the present invention can be prepared in any suitable manner. For example, the composition can be prepared by mixing together the appropriate divided components, optionally with one or more carriers, and then mixing the dry mixture with a liquid component (liquefier) ​​to form a liquid mixture. If the final product is a powder, the liquid mixture can then be homogenized, pasteurized, and optionally spray-dried. The composition may be homogenized before or after sterilization.

[0124] The nutritional compositions of the present invention can be administered to an individual, such as a human, e.g., an elderly person, in a therapeutically effective dose, which can be determined by one skilled in the art and can vary depending on a number of factors known to those skilled in the art, such as the severity of the condition and the weight and general condition of the individual.

[0125] In one embodiment of the invention, the nutritional composition is administered to a subject in combination with an exercise or physical activity regimen.

[0126] The nutritional composition of the present invention can be formulated in the form of an animal treat (e.g., biscuit) or dietary supplement for administration to an animal. The composition can be a dry composition (e.g., kibble), a semi-moist composition, a wet composition, or any mixture thereof. In another embodiment, the nutritional composition is a dietary supplement, such as a gravy, drinking water, drink, yogurt, powder, granule, paste, suspension, chew, morsel, treat, snack, pellet, pill, capsule, tablet, or other suitable delivery form.

[0127] The nutritional composition may be administered to an individual in an amount sufficient to prevent the onset of a cardiovascular disorder or at least partially reduce the risk of developing a cardiovascular disorder if the individual has not already developed a cardiovascular disorder, such an amount being defined as a "prophylactically effective dose."

[0128] The nutritional composition is preferably administered daily or at least twice a week as a nutritional supplement to the diet of an individual.In one embodiment, the composition is administered to an individual for several consecutive days.For example, the composition can be administered to an individual daily for at least 30, 60 or 90 consecutive days.As another example, the composition can be administered to an individual for a longer period of time, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 years.

[0129] In a preferred embodiment, the nutritional composition is administered to the individual for a period of at least 3 months, such as between 3 months and 1 year, preferably for at least 6 months.

[0130] The above dosing examples do not require uninterrupted daily administration. Rather, there may be several short interruptions in administration, such as a 2-4 day break during the administration period. The ideal duration of administration of the composition can be determined by one of skill in the art.

[0131] Cardiovascular disorders The present invention provides compounds, compositions and methods for preventing and / or treating cardiovascular disorders by reducing residual inflammatory risk.

[0132] Cardiovascular disorders affect the heart or blood vessels. The main cardiovascular disorder is atherosclerosis (also known as arteriosclerotic vascular disease), in which fatty patchy deposits (plaques or atherosclerotic plaques) develop in the walls of medium and large arteries, leading to reduced or blocked blood flow. Atherosclerosis is a form of arteriosclerosis (meaning hardening of the arteries). Arteriosclerosis interferes with the body's regulation of blood pressure, increasing the risk of hypertension. The stiffening of arteries prevents them from expanding to return blood pressure to normal. People with high blood pressure are at greater risk of stroke, heart attack, and kidney failure.

[0133] Atherosclerosis is a syndrome that affects arterial blood vessels and is a response to chronic inflammation in the arterial wall. It is mainly caused by the accumulation of macrophages and promoted by low-density lipoproteins (LDL, a plasma lipoprotein that carries cholesterol and triglycerides) without proper removal of fats and cholesterol from the macrophages by functional high-density lipoproteins (HDL). Atherosclerosis is also commonly referred to as hardening or furring of the arteries. This condition is caused by the formation of multiple plaques in the arteries.

[0134] When atherosclerosis affects the arteries that supply blood to the heart (coronary artery disease), this can cause chest pain (angina) or, if an area of ​​heart muscle is destroyed, a heart attack (myocardial infarction). Reduction in oxygen-rich blood flow to the heart muscle can cause heart failure (a disorder in which the heart pumps blood insufficiently), which can lead to reduced blood flow, back-up of blood in the veins and lungs (congestion), and other changes that can further weaken the heart. Failure of the coronary circulation to provide an adequate circulatory supply to the heart muscle and surrounding tissues is called coronary heart disease.

[0135] Atherosclerosis affecting the arteries to the brain can lead to stroke, which occurs when an artery to the brain becomes blocked or ruptures, causing death of an area of ​​brain tissue (cerebral infarction).

[0136] In terms of mortality, the main cardiovascular disorders are stroke and heart attack, but cardiovascular disorders also encompass conditions such as aortic aneurysm and peripheral vascular disease, and are responsible for clinical conditions including renal vascular disease, vascular dementia and retinal disease. Prevention of cardiovascular disorders is not only about reducing mortality, but also about preventing disability and improving quality of life.

[0137] It can be appreciated that the compounds, compositions and methods of the present invention may be useful in the prevention and / or treatment of atherosclerosis and / or related conditions, particularly in the prevention of the onset or progression of atherosclerosis.

[0138] Treatment method It will be appreciated that all references made herein to "treatment" include curative, palliative and prophylactic treatment, although references made in the context of the present invention to "prevention" more generally relate to prophylactic treatment. Treatment may also include arresting the progression of the severity of the disease.

[0139] The terms "treat", "treating", or "treatment" in reference to any disease or disorder, in one embodiment, refer to ameliorating the disease or disorder (i.e., delaying or preventing or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat", "treating", or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treat", "treating", or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treat", "treating", or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder. As used herein, a subject is "in need of treatment" if such a subject would derive a biological benefit, medical benefit, or quality of life benefit from such treatment.

[0140] subject The term "subject" refers to any animal, including humans and companion animals. Generally, the subject is a human, or a bird, cow, dog, horse, cat, goat, rat, sheep or pig. The subject can be a horse or a companion animal, such as a cat or dog. Preferably, the subject is a human.

[0141] The treatment of mammals, especially humans, is preferred, however, both human and veterinary treatment are within the scope of the invention.

[0142] For veterinary subjects, preferably the subjects are dogs, cats, and horses.

[0143] Administration Preferably, the compounds and compositions described herein are administered enterally.

[0144] Enteral administration may be oral, gastric, and / or rectal.

[0145] In one embodiment, administration is oral or gastric. In a preferred embodiment, administration is oral.

[0146] In general terms, administration of the combinations or compositions described herein may be, for example, by the oral route or by another route to the gastrointestinal tract, for example administration may be by tube feeding.

[0147] The subject may be a mammal, such as a human, dog, cat, horse, goat, cow, sheep, pig, deer, and a primate. Preferably, the subject is a human.

[0148] Sensory characteristics The present invention provides compounds that have improved organoleptic properties and are sources of butyrate. In particular, the compounds have improved odor and / or taste compared to butyric acid, butyrate salts, and / or tributyrin. In one embodiment, the compounds have improved taste compared to tributyrin. In one embodiment, the compounds have improved odor compared to butyrate salts (e.g., sodium butyrate).

[0149] In one embodiment, the improved sensory attribute is improved odor. In one embodiment, the improved sensory attribute is improved taste. In one embodiment, the improved sensory attribute is improved odor and improved taste. In one embodiment, the improved taste is reduced bitterness. EXAMPLES

[0150] Example 1 - Preparation of Butyrated Triglycerides (TAG) A composition containing butyrated TAG was produced by chemical transesterification between tributyrin and high oleic sunflower oil in the presence of a catalyst such as sodium methoxide. A molar excess of tributyrin relative to high oleic sunflower oil was used.

[0151] The three reagents, namely tributyrin, high oleic sunflower oil and catalyst, were mixed in a reactor under nitrogen atmosphere and then heated with stirring at 80° C. for 3 h. Upon completion of the reaction, the product was washed several times with water and then dried under vacuum (25 mBar, 60° C. for 2 h). The oil product obtained was then subjected to a decolorization step by the action of bleaching earth and purified either by short-path distillation (130° C., 0.001-0.003 mbar) or deodorization by injection of steam water (160° C., 2 mbar, 2 h).

[0152] The components of the resulting oil composition (mainly triglycerides) are shown in Table 1 below. The triglycerides are represented by the three fatty acids they contain. These fatty acids are represented by their lipid numbers: 4:0 for butyrate, 16:0 for palmitate, 18:0 for stearate, 18:1 for oleate, and 18:2 for linoleate. The central fatty acid is located in the sn-2 position of the triglyceride. As an example, 16:0-4:0-18:1 represents two different triglycerides, which include both molecules with butyrate in the sn2 position and palmitate in the sn-1 position and oleate in the sn-3 position or oleate in the sn-1 position and palmitate in the sn-3 position.

[0153] The TAG profile and positional isomers were analyzed by liquid chromatography coupled to a high-resolution mass spectrometer. The proportion of each lipid was assessed by liquid chromatography coupled to an evaporative light scattering detector (ELSD).

[0154] [Table 1]

[0155] In the composition samples, the two most abundant TAGs were 4:0-18:1-4:0 and 18:1-18:1-4:0, which together amounted to approximately 40-50 g / 100 g.

[0156] Example 2 - Odor characteristics of triglycerides containing butyrate moieties An odor comparison of a solution containing butyrate moiety-containing TAG (composed primarily of oleic and butyric fatty acids) was compared to a solution containing sodium butyrate.

[0157] Sample preparation Solutions containing butyrate moiety-containing TAG (see Example 1) or sodium butyrate were prepared and stored at 4° C. until presented to the sensory panel. Each 250 mL solution contained 600 mg butyric acid (equivalent to one capsule of sodium butyrate commercially available as a dietary supplement; concentration of 2.4 mg / mL) and 1% w / v BEBA Optipro 1 infant formula in acidified deionized water.

[0158] The samples were prepared the day before the test by placing 4 mL of each solution (TAG butyric acid solution; sodium butyrate solution) in an Agilent vial.

[0159] method A "2 vs 5 test" was conducted. In this test, five samples are presented to panelists. Panelists are asked to identify two samples that are different from the other three. The order of presentation of the samples is randomized to avoid presentation order bias.

[0160] In addition to the 2-to-5 point test, a comment section was provided for panelists to comment on the nature of the perceived difference (eg, odor intensity, odor quality).

[0161] result The five samples were presented simultaneously to the panelists, who were asked to remove the caps, smell, and then cap each vial in a given order. The results are shown in Table 2.

[0162] [Table 2]

[0163] P values ​​were calculated using a binomial test performed with the Fizz software (Biosystems, France).

[0164] Panelists who were able to distinguish between the correct responses (butyrate moiety-containing TAGs as opposed to sodium butyrate) described the sodium butyrate as having a "cheese" smell, whereas for the butyrate moiety-containing TAG samples, this "cheese" smell was greatly reduced and the odor was almost benign.

[0165] Example 3. Taste characteristics of triglycerides containing butyrate moieties Sensory benchmarking of solutions containing butyrate moiety-containing TAG (see Example 1), composed primarily of oleic and butyric fatty acids, was performed in comparison to a solution containing tributyrin.

[0166] Sample preparation One tablespoon (4.6 g) of BEBA Optipro1 infant formula was added to warm water (boiled water cooled as per instructions) to a final volume of 150 mL (approximately 3% w / v solution). Each TAG form of butyrate was weighed separately to provide 600 mg of butyrate, and infant formula was added to bring each solution to a final volume of 50 mL.

[0167] Solution A contained a butyrate moiety-containing TAG (see Example 1). Solution B contained tributyrin.

[0168] method Groups of panelists conducted repeated blind tastings.

[0169] The samples were prepared immediately prior to the preliminary bitterness evaluation, and each solution was vigorously shaken. Tasting cups, labeled A and B, were filled simultaneously with small amounts of each solution.

[0170] The two samples were presented simultaneously to panelists who were asked to taste the solutions by holding them in their mouths and spitting them out, and to rate their perceived bitterness on a scale of 0 to 10 (0 being no perception of bitterness, 10 being the most bitter taste imaginable).

[0171] result The bitterness of Solution A was rated by panelists as 4.33±1.52, mean±SD.

[0172] The bitterness of solution B was rated by panelists as 8.33±1.52, mean±SD.

[0173] These data show that the butyrate moiety-containing TAG compositions in infant formula were significantly less bitter compared to tributyrin in infant formula.

[0174] Example 4. Taste properties of 1,3-dibutyryl-2-palmitoylglycerol 1,3-Dibutyryl-2-palmitoylglycerol (BPB) was synthesized as a single compound using the following synthesis.

[0175] [ka]

[0176] When BPB was evaluated by a descriptive sensory panel, it was found to have no distinctive taste or odor.

[0177] Example 5. Digestion of triglycerides containing butyrate moieties 5.1 Emulsion preparation A 10 wt% oil-in-water emulsion stabilized with 0.3 wt% polyoxyethylene sorbitan monooleate (Tween® 80) was prepared by mixing Tween 80 into the oil phase at 40° C. and then mixing with the water phase. An ultrasonic probe homogenizer was then used to create the emulsion.

[0178] 5.2 Particle size measurement The droplet size of each lipid emulsion was measured by laser light scattering using a Mastersizer 3000 equipped with Hydro SM from Malvern Instruments (Malvern, Worcestershire, United Kingdom). The particle size of the emulsion is estimated as two values: volume surface mean diameter D3,2 (D3,2 1 / 4 Pnidi 3 / nidi 2) or volume length mean diameter D4,3 (D4,3 1 / 4 Pnidi 4 / nidi 3). The emulsion particle size result is the average of three measurements of two freshly prepared emulsions.

[0179] 5.3 In vitro digestion Lipid emulsions (2 mL) containing 200 mg of fat were subjected to in vitro gastrointestinal lipolysis. Digestion was carried out in a thermostated glass vessel (37° C.) in a pH-STAT assembly controlled by a TIM 856 bi-burette pH-STAT (Radiometer Analytical (France)). For gastric digestion, samples were incubated for 90 min at 37° C. and pH 5.5 with 8.5 mL of simulated gastric fluid (SGF) consisting of 150 mM NaCl, 450 U / mL pepsin, 18 U / mL rabbit gastric lipase. Digestion was started by adding 18 U / mL rabbit gastric lipase (TBU, activity against tributyrin assessed at pH 5.4).

[0180] The intestinal digestion step was carried out in a pH-STAT where the pH was kept constant at 6.8 by adding NaOH. A bile salt mixture (bile salts prepared in Tris buffer) and a calcium solution (20 mM Ca, 176.5 mM Tris, 150 mM NaCl) were added to the SGF sample mixture. The mixture was transferred to the pH-STAT and the pH was adjusted to about 6.78. The intestinal digestion step was started when the temperature reached 37±0.5°C. The pH was adjusted to pH 6.8 and incubated at this pH and temperature for 2 minutes before the addition of the pancreatin solution. The final composition of the intestinal fluid was 10 mM CaCl2, 12 mM mixed bile salts, 0.75 mM phospholipids, 150 mM NaCl, and 4 mM tris(hydroxymethyl)aminomethane buffer. The intestinal digestion step was carried out for 3 hours in a Radiometer titration manager. During the intestinal digestion phase, the digestion rate was followed using pH-STAT (TIM856, Radiometer) technique and expressed as titratable acid (not fatty acid) calculated by the following formula:

[0181] TA=V NaOH x0:05x1000 TA: total amount of titratable acid released, mmol, V NaOH : Volume of NaOH used to titrate the acid released in 3 hours, mL.

[0182] 5.6 Results Since dietary lipid digestion involves lipases from both the stomach and intestine, lipid digestibility was evaluated using two digestion models: i) porcine pancreatic lipase (PPL) in simulated intestinal fluid (SIF), and ii) sequential digestion in simulated gastric fluid (SGF) with rabbit gastric lipase (RGL) followed by porcine pancreatic lipase (PPL) in simulated intestinal fluid (SIF). All lipids were emulsified with polyoxyethylene sorbitan monooleate (Tween® 80) and had similar particle size distribution and specific surface area (Figure 2). This means that the difference in digestion mainly originates from the molecular structure of triglycerides.

[0183] Figure 1A-C i) shows the digestion by porcine pancreatic lipase (from spleen) in the presence of mixed bile and calcium of tributyrin (C4), high oleic sunflower oil (HOSFO, mostly C18:1) and the butyrate moiety-containing triglyceride "C4-C18:1" according to the invention, produced by chemical transesterification between tributyrin and high oleic sunflower oil (see Example 1) (SIF model). The lipids generally showed the same lipolysis behavior, with an initial rapid lipolysis period in the first 15 minutes, which gradually slowed down during the last 2.5 hours of simulated intestinal digestion. C4 triglycerides showed an initial maximum rate of lipolysis of 223 ± 59 μmol / min. The initial lipolysis rate in high oleic sunflower oil, 34.5 ± 2.3 μmol / min, was significantly lower than that of the short-chain triglycerides (p < 0.0001). C4-C18:1 showed an initial hydrolysis rate of 153±47 μmol / min between C4 and C18:1. Taken together, it can be seen that all triglycerides are rapidly and fully digested in the presence of porcine pancreatic lipase.

[0184] These triglycerides were then digested in a sequential SGF(RGL)SIF(PPL) model. Digestion in the SIF section is shown in Fig. 1A-C ii). Measurements in the stomach section were not performed due to limited ionization of the fatty acids of interest. Compared to digestion in SIF alone, C4 and C18:1 triglycerides generally released smaller amounts of titratable acid during 3 h of digestion. The effect was greatest with tributyrin, which has a significantly (p<0.0001) lower initial lipolysis rate of 44.1±8.8 μmol / min during SGF-SIF digestion compared to 223±59 μmol / min for SIF alone. The total amount of acid released after SGF-SIF digestion of tributyrin, 381±20 μmol, is almost one-third of the amount released after digestion in SIF alone, 958±12.5 μmol. These results clearly demonstrate that digestion of tributyrin in the model stomach is substantial.

[0185] After sequential exposure to SGF and SIF, the rate of SIF lipolysis of butyrate-containing triglyceride C4-C18:1 was 124 ± 20 μmol / min, showing a slight, but not significant, decrease compared to SIF alone (124 ± 20 μmol / min). The most interesting observation is that the decrease in SIF lipolysis caused by pre-exposure to RGL is influenced by the secondary fatty acid chain length. Originally, tributyrin reduced total fatty acid release during SIF lipolysis by 60.2% (147 ± 7.6 μmol) after pre-exposure to RGL in SGF. In comparison, C4-C18:1 transesterified triglyceride showed a decrease of 6.1% (45 ± 7.6 μmol).

[0186] The overall lipid digestion extent of the three triglycerides after both SIF and SGF-SIF is shown in Figure 2 using direct and back titration. Many fatty acids are only partially ionized at pH 6.8, and direct titration only gives a partial picture of the lipid digestion extent, so back titration to pH 11.5 or GC-FAME analysis is required to estimate the overall extent of digestion. Back titration results for the three triglycerides show that tributyrin and butyrate moiety-containing triglyceride C4-C18:1 were 101.5±0.9% and 101±1.6% digested, respectively. Complete digestion indicates the release of three fatty acids per molecule, while high oleic sunflower oil was 72.3±2% digested, indicating the release of two fatty acids per molecule.

[0187] In general, it was found that tributyrin was fully hydrolyzed in the stomach, whereas high oleic sunflower oil triglycerides were very limitedly hydrolyzed in the stomach. Surprisingly, it was found that the extent of gastric lipolysis of C4 fatty acids was reduced by butyrate moiety-containing triglycerides made by transesterification of C4 with long chain fatty acids (C4-C18:1). Tributyrin was lipolyzed by gastric lipase to approximately 60%, as shown by the reduction in total fatty acid release during SIF lipolysis after pre-exposure to RGL in SGF. In comparison, C4-C18:1 butyrate moiety-containing triglycerides showed only a 6.1% reduction in total fatty acid release in SGF-SIF. These results suggest that transesterification of C4 with long-chain fatty acids (C4-C18:1) modulates the release of butyrate by delaying its release in the intestine after digestion rather than in the stomach, and that lipid design to this structure alters the timing (but not the degree) of short-chain fatty acid delivery to the gastrointestinal tract.

[0188] All publications mentioned in the above specification are incorporated herein by reference. Various modifications and alterations of the disclosed methods, cells, compositions, and uses of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been disclosed in connection with certain preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the disclosed modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the following claims.

Claims

1. 1. A compound having the formula: or a combination thereof for use in the prevention or treatment of a cardiovascular disorder in a subject. 【Chemistry 1】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , and R ６ are independently long-chain fatty acids having 16 to 20 carbons.

2. 1. A composition comprising a compound having the formula: 【Chemistry 2】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , and R ６ are independently long-chain fatty acids having 16 to 20 carbons.

3. 3. The composition for use according to claim 2, wherein the composition comprises the compound having formula (1), the compound having formula (2), the compound having formula (3), and the compound having formula (4).

4. 4. The composition for use according to claim 2 or 3, wherein the compound having formula (1), the compound having formula (2), the compound having formula (3), and the compound having formula (4) constitute at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% by weight of the total triglycerides of the composition.

5. 5. The composition for use according to any one of claims 2 to 4, wherein the compound having formula (1), the compound having formula (2), the compound having formula (3), and the compound having formula (4) constitute at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% by weight of the total butyrate moiety-containing triglycerides in the composition.

6. A composition for use according to any one of claims 2 to 5, wherein tributyrin constitutes less than 10% by weight of the total amount of triglycerides in the composition, preferably less than 8% by weight, more preferably less than 5% by weight of the total amount of triglycerides in the composition.

7. The composition for use according to any one of claims 2 to 6, wherein the composition further comprises dietary fibre.

8. The composition for use according to any one of claims 2 to 7, wherein the composition is a nutritional composition, a dietary supplement, or a pet care product.

9. R １ , R ２ , R ３ , R ４ , R ５ , and / or R ６ is an unsaturated fatty acid, preferably a monounsaturated fatty acid, or a compound or combination thereof for use according to claim 1, or a composition for use according to any one of claims 2 to 8.

10. R １ , R ２ , R ３ , R ４ , R ５ , and / or R ６ is selected from the group consisting of oleic acid, palmitic acid, or linoleic acid, preferably R １ , R ２ , R ３ , R ４ , R ５ , and R ６ A compound for use according to claim 1 or claim 9, or a combination thereof, or a composition for use according to any one of claims 2 to 9, wherein each of

11. A compound for use according to any one of claims 1, 9 or 10 or a combination thereof, or a composition for use according to any one of claims 2 to 10, for use in the treatment or prevention of atherosclerosis, coronary heart disease, myocardial infarction, angina pectoris, stroke and / or heart failure.

12. 12. A compound or a combination thereof or a composition for use according to claim 11 for use in the prevention of atherosclerosis.

13. A method for the treatment or prevention of cardiovascular disorders comprising administering to a human or animal subject an effective amount of a compound according to any one of claims 1 or 9-12 or a combination thereof, or a composition according to any one of claims 2-12.

14. 14. The method for treating or preventing cardiovascular disorders according to claim 13, wherein the cardiovascular disorder is selected from the group consisting of atherosclerosis, coronary heart disease, myocardial infarction, angina pectoris, stroke, and / or heart failure.

15. 15. The compound or combination thereof for use according to any one of claims 1 or 9 to 12, or the composition for use according to any one of claims 2 to 12, or the method according to claim 13 or 14, wherein said compound or combination thereof has improved organoleptic properties compared to butyric acid, tributyrin and / or butyrate salts.

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