Pharmaceutical compositions comprising curcuminoids, modified starch and / or acacia gum and saponins

Abstract

The present invention relates to the use of improved curminoid compositions for reducing LPS levels in the blood, reducing endotoxemia, maintaining the intestinal barrier, treating, reducing and / or preventing leaky gut syndrome, reducing intestinal lipid absorption, reducing ApoB48 levels in the blood, and / or treating, reducing and / or preventing dyslipidemia in a subject.

Description

[Technical Field]

[0001] The present invention relates to certain compositions comprising curcuminoids, acacia gum and quillaja that have improved effects on reducing blood LPS levels, reducing blood ApoB48 levels, reducing endotoxemia, maintaining the intestinal barrier, and / or treating, reducing and / or preventing leaky gut syndrome.

[0002] The present invention relates to certain compositions comprising curcuminoids, acacia gum and quillaja that have improved effects in reducing intestinal lipid absorption, reducing blood ApoB48 levels, and / or treating, reducing and / or preventing dyslipidemia. [Background technology]

[0003] Turmeric is a widely used spice and coloring / flavoring substance extracted from the rhizome of the plant (Curcuma longa), also known as turmeric. It has been used for centuries in traditional medicine in Asian countries and has been shown to improve many health conditions. Turmeric is on the U.S. Food and Drug Administration's (FDA) list of generally recognized as safe (GRAS) substances.

[0004] Turmeric has been found to be effective when given by different routes, including topically, orally, or by inhalation, depending on the intended use. The primary component of turmeric is curcumin (diferuloylmethane), which comprises 70-85% of the total curcuminoid content, with demethoxycurcumin and bis-demethoxycurcumin comprising the remainder (Aggarwal, B.B., & Shishodia, S. (2004). Annals of the New York Academy of Sciences, 1030, 434-441). Curcumin and curcuminoids have been extensively investigated due to their antioxidant and anti-inflammatory properties, particularly for their potential efficacy in regulating various health conditions. Turmeric (Curcuma longa) extract has a long history of use worldwide with a good safety profile. However, to be effective, very high doses of turmeric standardized extract (up to 6000 mg) or enhanced formulations (600-2500 mg) need to be administered.

[0005] Patent document 1 (WO02 / 02138 A1) describes a method for the prevention and / or treatment of endotoxemia associated with inflammatory bowel disease, which comprises administering an effective amount of a probiotic to a mammal in need of such treatment.

[0006] Patent document 2 (CN106511353 A) describes the use of triterpene compounds in the preparation of medicines for inhibiting the synthesis and secretion of intestinal ApoB48, particularly for the preparation of drugs to combat hyperlipidemia, cardiovascular and cerebrovascular diseases, atherosclerosis, etc.

[0007] In Non-Patent Document 1, Akira Asai et al. describe the effect of high doses of curcuminoids on lipid accumulation in the liver of rodents (Dietary Curcuminoids Prevent High-Fat Diet-Induced Lipid Accumulation in Rat Liver and Epididymal Adipose Tissue, The Journal of Nutrition, Volume 131, Issue 11, November 2001, Pages 2932-2935). [Prior art documents] [Patent documents]

[0008] [Patent Document 1] WO02 / 02138 A1 [Patent Document 2] CN106511353 A

[0009] [Non-Patent Document 1] Dietary Curcuminoids Prevent High-Fat Diet-Induced Lipid Accumulation in Rat Liver and Epididymal Adipose Tissue, The Journal of Nutrition, Volume 131, Issue 11, November 2001, Pages 2932-2935 Summary of the Invention

[0010] SUMMARY OF THE INVENTION The present inventors have surprisingly found that certain compositions comprising curcuminoids, acacia gum, and quillaja have improved effects on reducing blood LPS levels, reducing endotoxemia, maintaining the intestinal barrier, and / or treating, reducing, and / or preventing leaky gut syndrome.

[0011] The present inventors have surprisingly found that certain compositions comprising curcuminoids, acacia gum, and quillaja have improved effects in reducing intestinal lipid absorption, reducing blood ApoB48 levels, and / or treating, reducing, and / or preventing dyslipidemia.

[0012] As the examples herein demonstrate, unlike standard turmeric extracts, the compositions of the present invention have positive effects on reducing blood LPS levels, reducing endotoxemia, maintaining the intestinal barrier, and / or treating, reducing, and / or preventing leaky gut syndrome, even at significantly lower doses of the active compounds. Furthermore, the examples of the present invention surprisingly demonstrate that the compositions of the present invention reduce blood ApoB48 levels, thereby reducing intestinal lipid absorption and dyslipidemia. These effects were observed using a 10- to 20-fold reduction in the daily active dose of curcuminoids known in the art.

[0013] The reduction of effective daily dosage has the additional advantage that the dosage format can be reduced (i.e., smaller pills can be produced) with the same effect.Another advantage is that the administration of the active compound (curcuminoid) can be presented as a single dosage in one daily dose.The presentation of the composition of the present invention in a smaller dosage, along with the possibility of one single daily dose of the active compound, will have a positive effect on liver and / or cardiovascular health.

[0014] Thus, in a first aspect, the present invention provides a composition comprising i) a curcuminoid, ii) modified starch and / or acacia gum, and iii) one or more saponins for use in reducing blood LPS levels, reducing endotoxemia, maintaining the intestinal barrier and / or treating, reducing and / or preventing leaky gut syndrome.

[0015] In a second aspect, the present invention provides a composition comprising i) a curcuminoid, ii) modified starch and / or acacia gum, and iii) one or more saponins for use in reducing intestinal lipid absorption, reducing blood ApoB48 levels, and / or treating, reducing and / or preventing dyslipidemia.

[0016] In a third aspect, the present invention provides the use of a composition comprising i) a curcuminoid, ii) modified starch and / or acacia gum, and iii) one or more saponins for use in reducing blood LPS levels, reducing endotoxemia, maintaining the intestinal barrier and / or treating, reducing and / or preventing leaky gut syndrome.

[0017] In a further aspect, the present invention provides use of a composition comprising i) a curcuminoid, ii) modified starch and / or acacia gum, and iii) one or more saponins for use in reducing intestinal lipid absorption, reducing blood ApoB48 levels, and / or treating, reducing and / or preventing dyslipidemia.

[0018] In a further aspect, the present invention provides a method for maintaining liver and / or cardiovascular health, comprising administering to a subject in need thereof an effective amount of a composition comprising: i) a curcuminoid; ii) modified starch and / or acacia gum; and iii) one or more saponins.

[0019] Details, examples, and preferences described herein with respect to any one of the described aspects of the invention apply equally to all aspects of the invention. All combinations of the embodiments, examples, and preferences described below, in any variations, are encompassed by the invention unless otherwise stated herein or clearly contradicted by context. [Brief explanation of the drawings]

[0020] [Figure 1]Figure 1 shows blood translocation of LPS. Blood levels of LPS before and 5 hours after fat challenge (time 0). For LPS, no main treatment effect on post-meal response was observed, while there was a trend for a baseline effect (p=0.06) on LPS levels for the test formulation according to the invention (Supplement A) when compared to control (Supplement B). [Figure 2] Figure 2 shows chylomicron production. ApoB48 is a chylomicron-specific biomarker that incorporates LPS and lipids into blood translocation. A significant effect of the test formulation according to the present invention (Supplement A) was found in postprandial ApoB48 concentrations (p<0.001) and ApoB48 AUC (p=0.04) compared to the control (Supplement B). [Figure 3] Figure 3 is a diagram depicting the study design. DETAILED DESCRIPTION OF THE INVENTION

[0021] Detailed Description of the Invention It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the embodiments as claimed. The use of the singular herein includes the plural unless expressly stated otherwise. As used herein, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "includes" and "included," is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, etc., are hereby expressly incorporated by reference in their entirety as well as for the portions of the documents discussed herein.

[0022] According to the present invention, there is provided a composition comprising i) a curcuminoid, ii) modified starch and / or acacia gum, and iii) one or more saponins (e.g., quillaja saponin) for use in reducing blood LPS levels, reducing endotoxemia, maintaining the intestinal barrier, and / or treating, reducing, and / or preventing leaky gut syndrome.

[0023] Such compositions are hereinafter referred to as "compositions for use according to the invention" or "compositions according to the invention".

[0024] Accordingly, the present invention provides a composition comprising: i) a curcuminoid; ii) modified starch and / or acacia gum; and iii) one or more saponins (e.g., Quillaja saponin) for use in reducing intestinal lipid absorption, reducing blood ApoB48 levels, and / or treating, reducing, and / or preventing dyslipidemia.

[0025] The present invention also provides the use of a composition comprising i) a curcuminoid, ii) modified starch and / or acacia gum, and iii) one or more saponins (such as quillaja saponin) for use in reducing blood LPS levels, reducing endotoxemia, maintaining the intestinal barrier, and / or treating, reducing, and / or preventing leaky gut syndrome.

[0026] The present invention also provides use of a composition comprising i) a curcuminoid, ii) modified starch and / or acacia gum, and iii) one or more saponins for use in reducing intestinal lipid absorption, reducing blood ApoB48 levels, and / or treating, reducing, and / or preventing dyslipidemia.

[0027] Such a use may be referred to hereinafter as "use of the present invention."

[0028] Also provided is a method for reducing blood LPS levels, reducing endotoxemia, maintaining intestinal barrier integrity and / or treating, reducing and / or preventing leaky gut syndrome in a subject in need thereof, comprising administering to the subject effective amounts of a composition comprising: i) a curcuminoid; ii) modified starch and / or acacia gum; and iii) one or more saponins (e.g., Quillaja saponin).

[0029] The present invention also provides a method for reducing blood LPS levels, reducing endotoxemia, maintaining the intestinal barrier, and / or treating, reducing, and / or preventing leaky gut syndrome in a subject in need thereof, comprising administering to the subject effective amounts of a composition comprising: i) a curcuminoid; ii) modified starch and / or acacia gum; and iii) one or more saponins (e.g., Quillaja saponin).

[0030] Such a method may be referred to hereinafter as the "method of the present invention."

[0031] In certain embodiments of the compositions, uses, or methods for use of the present invention, the compositions comprising cruminoids can be administered or used to provide cruminoids in an amount of from about 50 mg / dose to about 300 mg / dose, e.g., about 60 mg / dose, 70 mg / dose, 80 mg / dose, 90 mg / dose, 100 mg / dose, 150 mg / dose, 200 mg / dose, or 300 mg / dose.

[0032] The compositions of the present invention can be used to downregulate the response to LPS and thus treat or prevent the development of endotoxemia in a patient.

[0033] Endotoxin (lipopolysaccharide, LPS) is a major component of the outer membrane of Gram-negative bacteria and is known to be a contributing factor to inflammation [Catorce MN, Gevorkian G. LPS-induced Murine Neuroinflammation Model: Main Features and Suitability for Pre-clinical Assessment of Nutraceuticals. Curr. Neuropharmacol. 2016;14:155-164]. LPS can originate, for example, from the skin, mucous membranes, or local sites of bacterial infection, but the gut microbiota is thought to be the main natural reservoir of pro-inflammatory endotoxins in the body. Endotoxin (LPS) is released upon bacterial death, and the dissociated endotoxin can then cross the gastrointestinal barrier and end up in the bloodstream. The presence of LPS in the bloodstream is defined as endotoxemia.

[0034] Briefly, the endotoxic metabolic pathway involves the binding of circulating LPS to LPS-binding protein (LBP) and its transfer to the CD14 receptor, which exists in both membrane-anchored (mCD14) and soluble circulating (sCD14) forms. The LPS-LBP-CD14 complex initiates the secretion of proinflammatory cytokines, such as interleukin-6 (IL-6) or tumor necrosis factor α (TNFα), via a TLR4-dependent mechanism.

[0035] Although LPS is detectable in low concentrations in the circulation of healthy individuals, there is evidence that LPS levels transiently increase after ingestion of a fatty meal [Brown BI Nutritional Management of Metabolic Endotoxemia: A Clinica l Review. Altern. Ther. Health Med. 2017;23:42-54]. This type of endotoxemia is defined as "metabolic endotoxemia," in contrast to other causes of endotoxemia.

[0036] Metabolic endotoxemia has been proposed as a major cause of inflammation, including chronic low-grade inflammation. Indeed, animal and experimental studies have shown that the postprandial state can induce an inflammatory response that is closely associated with increased circulating levels of LPS.

[0037] In some embodiments, the endotoxemia is postprandial endotoxemia. In some embodiments, the postprandial endotoxemia is after ingestion of dietary fat, such as a high saturated fat meal. In some embodiments, the endotoxemia is postprandial endotoxemia after ingestion of a fatty meal.

[0038] In some embodiments, the endotoxemia is associated with inflammatory bowel disease.

[0039] Elevated levels of LPS are associated with a wide range of diseases, including obesity and coronary artery disease. (Brown BI Nutritional Management of Metabolic Endotoxemia: A Clinical Review. Altern. Ther. Health Med. 2017;23:42-54).

[0040] Accordingly, in one aspect, the present invention relates to a method for maintaining liver and / or cardiovascular health comprising administering to a subject in need thereof an effective amount of a composition comprising: 1) a curcuminoid; 2) modified starch and / or acacia gum; and 3) one or more saponins.

[0041] Thus, in one aspect, the present invention relates to a method for the treatment or prevention of obesity, and / or the treatment or prevention of coronary artery disease, comprising administering to a subject in need thereof an effective amount of a composition comprising i) a curcuminoid, ii) modified starch and / or acacia gum, and iii) one or more saponins.

[0042] LPS may be measured using well-established methods and kits such as those described in the Results section of this text or at, for example, http: / / assets.thermofisher.com / TFS-Assets / BID / Reference-Materials / highly-sensitive-assay-endotoxin-detection-quantitation-variety-sample-types-white-paper.pdf.

[0043] In this specification, "leaky gut syndrome" or "leaky gut syndrome (LGS)" refers to the phenomenon in which intestinal mucosal cells maintain a certain gap between cells, and polymeric materials shuttle through the gaps during the digestive and absorptive processes, increasing the permeability of the intestinal mucosa. "Leaky gut syndrome" refers to symptoms caused by intestinal dysfunction, which results in leakage of polymeric materials from the blood into the intestinal lumen or direct infiltration of polymeric materials from the lumen into the bloodstream. These symptoms manifest in various clinical conditions, including aging, allergies, multiple trauma, rheumatoid arthritis, inflammatory bowel disease, chronic fatigue syndrome, and irritable bowel syndrome. In addition, increased permeability or damage to the intestinal mucosa allows pathogens, antigens, and corrosive substances to enter the intestinal mucosa, triggering various inflammatory responses. Furthermore, endotoxins enter the bloodstream, causing bacterial translocation and endotoxemia, leading to various inflammatory and immune responses.

[0044] Although the exact cause of leaky gut syndrome has not been discovered, it may be caused by long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) as painkillers, combined use of antibiotics and steroids, radiation therapy or chemotherapy as anti-cancer treatment, changes in the composition of normal intestinal flora in the intestinal tract, fungal overgrowth in the intestinal tract, excessive food intake, consumption of spoiled food, or ingestion of heavy metals or toxins, excessive consumption of irritating foods or food allergies, excessive alcohol intake, multiple trauma, exposure to acute or chronic psychological stress, chronic bacterial, parasitic, or yeast infections, etc.

[0045] Specifically, a composition for alleviating, preventing, or treating leaky gut syndrome may also be referred to as a composition having the effect of increasing, improving, preventing, alleviating, suppressing, and treating intestinal permeability due to the various causes described above. The composition has the effect of alleviating, preventing, and treating leaky gut syndrome, which occurs when increased intestinal permeability causes polymeric substances in the blood to leak into the intestinal lumen or polymeric substances in the lumen to enter the branched bloodstream, leading to various diseases. Prevention or treatment of leaky gut syndrome may refer to the inhibition of the phenomenon in which the gaps between intestinal mucosal cells loosen, thereby increasing the permeability of the intestinal mucosa, allowing polymeric substances to pass back and forth.

[0046] As used herein, the term "effective amount" refers to the amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal, or human that a researcher, veterinarian, physician, or other clinician considers to be sufficient to induce alleviation of associated symptoms. The effective amount and frequency of administration of the active ingredient of the present invention will vary depending on the desired effect. Therefore, the optimal dosage to be administered can be easily determined by those skilled in the art, and can be adjusted depending on various factors, such as the disease or condition to be treated (e.g., the severity of symptoms of inflammatory bowel disease, the degree of intestinal permeability in leaky gut syndrome), the content of the active ingredient and other components contained in the composition, the type of formulation, the patient's age, weight, general health, sex, and diet, the time of administration, the route of administration and excretion rate of the composition, the duration of treatment, and concomitant medications.

[0047] Apolipoprotein B48 (ApoB48) is an apolipoprotein essential for lipid absorption in the small intestine. Dietary lipids are taken up by small intestinal epithelial cells, synthesized by ApoB48 into chylomicrons, and secreted into the blood via the lymphatic circulation. ApoB48 is a recognized characteristic marker of intestinal lipoproteins. Studies have shown that in some pathological conditions, such as hyperlipidemia, coronary heart disease, insulin resistance, diabetes, and other metabolic diseases, patients exhibit abnormal fasting plasma ApoB48 levels. Elevated plasma ApoB48 levels lead to the deposition of triglyceride-rich lipoprotein remnants in blood vessel walls, resulting in the formation of atherosclerotic plaques. Therefore, regulating intestinal ApoB48 levels can help improve exogenous lipid absorption, thereby reducing the risk of cardiovascular diseases such as hyperlipidemia. The accumulation of residual lipoproteins, particularly gut-derived chylomicron remnants (Apob48), is associated with impaired lipid and glucose metabolism and ASCVD (atherosclerotic cardiovascular disease) events.

[0048] Therefore, the present invention also relates to the use of a composition comprising i) a curcuminoid, ii) modified starch and / or acacia gum, and iii) one or more saponins for the treatment, reduction and / or prevention of atherosclerotic cardiovascular disease.

[0049] A method for treating, reducing and / or preventing atherosclerotic cardiovascular disease, comprising administering to a subject in need thereof an effective amount of a composition comprising: i) a curcuminoid; ii) modified starch and / or acacia gum; and iii) one or more saponins.

[0050] In one embodiment, the subject is a healthy subject. In one embodiment, the subject is a subject with IBS.

[0051] The composition of the invention, the composition according to the Use of the Invention, the composition according to the Method of the Invention may be in the form of a colloidal suspension, an emulsion, or a solid, for example in the form of a powder.

[0052] As used herein, the term "emulsion" refers to a dispersion of droplets of one liquid in another liquid that has no solubility or miscibility therein.

[0053] Although "colloid" and "emulsion" are sometimes used interchangeably, as used herein, the term emulsion applies when a liquid phase is dispersed in another liquid. A colloid is a dispersion of particles of one substance in another substance, in which the particles do not settle. The particles in a colloid can be of any phase of matter. Thus, while an emulsion is a type of colloid, not all colloids are emulsions. In some embodiments, the compositions of the present invention form a colloidal suspension of a solid, such as curcuminoid particles, in a liquid.

[0054] In some embodiments, the compositions of the present invention do not include fenugreek. For example, in some embodiments, the compositions of the present invention do not include fenugreek fiber (i.e., fiber obtained or obtainable from fenugreek).

[0055] The compositions of the present invention may contain small amounts, e.g., less than 5% by weight of the composition, or less than 2.5% by weight of the composition, of polyols and / or low molecular weight sugars, preferably having 1 or 2 monosaccharide units. Alternatively, the compositions of the present invention may be free of polyols and / or low molecular weight sugars, such as having 1 or 2 monosaccharide units, i.e., some compositions do not contain polyols and / or low molecular weight sugars, such as having 1 or 2 monosaccharide units.

[0056] The compositions of the present invention include particles having an average diameter (or mean diameter) of about 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm, 1,000 nm, 1,100 nm, 1,200 nm, 1,300 nm, 1,400 nm, or 1,500 nm, to about 9,000 nm, 8,000 nm, 7,000 nm, 6,000 nm, 5,000 nm, 4,000 nm, 3,000 nm, or 2,000 nm, for example, about 1,000 nm to about 6,000 nm. The particles may also have an average diameter of about 200 nm to about 600 nm, or about 300 nm to about 500 nm, or about 400 nm, as determined by laser diffraction.

[0057] For example, when the composition is in the form of an emulsion or colloid, the composition can contain particles with an average diameter of about 550 nm to about 700 nm, and particles with an average diameter of about 100 nm to about 250 nm, resulting in an average diameter of about 400 nm. The average particle size is determined by laser diffraction (dynamic light scattering or DLS).

[0058] When the composition is in a solid form, such as a powder, the composition can include particles having an average diameter (or mean size) of from about 1,000 nm to about 6,000 nm, such as from about 2,000 nm to about 4,000 nm. The average particle size is determined by laser diffraction (dynamic light scattering or DLS).

[0059] The particles in the compositions of the present invention may be in the form of micelles.

[0060] In compositions of the present invention, for example when the composition is in solid form, particles may be formed using techniques known in the art such as spray drying.

[0061] After the particles are formed (eg, after drying, such as by spray drying), they may be crushed and / or milled (eg, ball milled) to obtain a more uniform size.

[0062] The size and morphology of the loaded curcumin micelles may be analyzed by dynamic light scattering (DLS), for example, using a Mastersizer 3000. The Mastersizer 3000 uses the technique of laser diffraction to measure the particle size and particle size distribution of a material. This is done by measuring the intensity of light scattered when a laser beam passes through a dispersed particulate sample.

[0063] The curcuminoids in the compositions of the present invention may be obtained from any source, however it is preferred that the curcuminoids are obtained from natural sources, i.e., plant-derived rather than synthetic.

[0064] In the methods or uses described herein, the curminoid may be selected from the group consisting of curcumin, demethoxycurcumin, bisdemethoxycurcumin, any of their phase I and phase II metabolites, and any of their mixtures. For example, the phase I and / or phase II metabolite may be curcumin glucuronide, curcumin sulfate, DMC glucuronide, DMC sulfate, BDMC glucuronide, BDMC sulfate, tetrahydrocurcumin (THC), THC glucuronide, THC sulfate, hexahydrocurcumin (HHC), HHC glucuronide, HHC sulfate, or a mixture thereof.

[0065] In the uses, methods, or compositions for use described herein, the curcuminoids may be in their unmetabolized form (i.e., free form), such as curcumin, DMC, and BDMC, which have not been glucuronidated or sulfated.

[0066] The compositions of the present invention may comprise at least about 10%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% by weight of curcuminoids, based on the total weight of the composition.

[0067] For example, in the methods or uses described herein, cruminoids may be present in the composition in an amount of from about 20% to about 60% by weight of the composition, such as from about 25% to about 50% by weight, or from about 28% to about 48% by weight, based on the total weight of the composition.

[0068] For example, in the methods or uses described herein, the curcuminoid may be present in the composition in an amount from about 30 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg or 90 mg to about 1,500 mg, 1,400 mg, 1,200 mg, 1,100 mg, 1,000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 400 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg or 95 mg, such as from about 70 mg to about 300 mg, or from about 70 mg to about 200 mg, or from about 70 mg to about 100 mg, such as 90 mg.

[0069] Curcuminoids may be provided in the form of a turmeric extract or purified extract obtained by extraction of turmeric (Curcuma longa) roots (rhizomes) followed by an optional purification step. Preferably, the extract or purified extract contains from about 30% to about 100% curcuminoids, e.g., from about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% to about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, or 45% curcuminoids (% by weight based on the total weight of the extract).

[0070] Turmeric may be extracted using alcohol-based extraction solvents such as water / alcohol mixtures or alcohol, organic-based extraction solvents, or other techniques and solvents that allow for a high yield of turmeric. For example, the alcohol-based extraction solvent may be water / methanol (i.e., a mixture of water and methanol), or water / ethanol (i.e., a mixture of water and ethanol), or methanol, or ethanol.

[0071] When the extraction solvent comprises a mixture of water and alcohol, the ratio of water to alcohol can be from about 25:75 to about 1:99, such as from about 20:80 to about 5:95, or about 10:90, etc. For example, the extraction solvent can be a water / ethanol ratio of from about 25:75 to about 1:99, such as from about 20:80 to about 5:95, or about 10:90.

[0072] The turmeric extract may then be further refined to provide an extract of curcuminoids containing from about 30% to about 100%, e.g., from about 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% to about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, or 45% curcuminoids (% by weight based on the total weight of the extract).

[0073] Purification of the extract may be carried out using techniques known in the art. Typically, the extract is purified using an alcohol-based solvent such as 100% methanol or 100% ethanol.

[0074] The turmeric extract may optionally be dried to remove excess solvent.

[0075] In certain embodiments of the compositions, uses, or methods for use of the present invention, curcuminoids are provided by extraction and optionally purification (such as ethanol extraction) from turmeric (Curcuma longa) root (rhizome), oleoresin turmeric root, defatted oleoresin turmeric root, and mixtures thereof.

[0076] When the curcuminoid is provided in the form of a turmeric extract as defined above, the composition may comprise from about 30% to about 80% turmeric extract by weight of the composition, such as from about 35% to about 45% by weight. For example, the composition comprises from about 35% (i.e., 35%) to about 45% turmeric extract by weight of the composition, wherein the turmeric extract comprises from about 85% to about 95% curcuminoids by weight of the turmeric extract, providing a composition comprising from about 30% (i.e., 30%) to about 43% curcuminoids by weight of the composition.

[0077] The curminoids may be provided as a liquid or powder, preferably as a powder, for example, powdered turmeric extract.

[0078] As used herein, the term "curcuminoid" encompasses curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). For example, a turmeric extract may contain about 70% to about 85% (e.g., about 75% to about 80%) curcumin, about 10% to about 25% (e.g., about 15% to about 20%) DMC, and about 0% to about 10% BDMC. For example, a composition may contain about 60 mg to about 90 mg of curcuminoids, together with about 54 mg to about 69 mg of curcumin, and about 6 mg to about 11 mg of DMC and BDMC. In preferred embodiments, the compositions may be administered or used to provide curcuminoids in an amount of about 70, 80, 90, 95, 100, 150, 200, 250 mg / day to about 1,500, 1,400, 1,300, 1,200, 1,100, 1,000, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300 mg / day, e.g., about 70 mg / day to about 150 mg / day, e.g., about 70 mg / day to about 90 mg / day of curcuminoids. In one embodiment, the ratio of curcumin to DMC / BDMC is 7:3 to 8:2. In a preferred embodiment, the curcumin provided is from about 54 mg / day to about 69 mg / day, and the DMC and BDMC are from 16 mg / day to about 21 mg / day.

[0079] In the methods or uses described herein, gum acacia (also called gum arabic) may be present in the composition in an amount from about 30%, 35%, 40%, 45%, 50%, 55% to about 85%, 80%, 75%, 70%, 65%, 60% by weight of the composition, for example from about 50% to about 60% by weight of the composition, or about 58% by weight of the composition.

[0080] In the methods or uses described herein, the modified starch may be present in the composition in an amount of about 40% to about 65% by weight of the composition, for example about 50% to about 60% by weight of the composition, or about 58% by weight of the composition.

[0081] Saponins are a group of naturally occurring glycosides found primarily in plants. They contain a non-carbohydrate aglycone coupled to a sugar unit. Saponins are divided into two groups: steroidal and triterpene saponins. Over 100 steroidal saponins and an even larger number of triterpene saponins have been identified to date (K. Hostettmann, & A. Marston, Saponins (Cambridge University) Press, 1995). As used herein, the term "saponin(s)" includes one or more saponins of natural origin (such as Quillaja or yucca saponins) or synthetic origin, as well as extracts obtained or obtainable from any plant, animal, or bacterial source of saponins, such as Quillaja, Yucca, etc. The saponin in the compositions of the present invention may be of natural or synthetic origin. It may be one or more saponins of the same or different origin. For example, the saponin(s) may be derived from soybean, bean, pea, solanum and allium species, tomato, asparagus, tea, peanut, spinach, sugar beet, yam, blackberry, licorice root, primrose root, senega root, tea, ginseng, Quillaja (such as Quillaja saponaria), Yucca (such as Yucca saponaria), or other saponins of the genus Yucca. In one embodiment, the one or more saponins are Quillaja saponin(s). In one preferred embodiment, the saponin is not ginger saponin. The one or more saponins used in the present invention may be highly purified or may be natural extracts containing varying concentrations of saponins.

[0082] In certain embodiments, the one or more saponin(s) are selected from purified Quillaja saponin(s) of natural or synthetic origin, or extracts obtained or obtainable from the Quillaja genus, and mixtures thereof.

[0083] As used herein, the terms "Quillaja saponin(s)," "yucca saponin(s)," and the like refer to one or more saponins, which may be obtained from or obtainable from any member of the Quillaja or Yucca genus, or any saponin-containing plant, such as those described above. The Quillaja saponin or mixture of Quillaja saponins (or yucca saponin or mixture of yucca saponins) may be synthetic or naturally derived.

[0084] As will be understood by those skilled in the art, the term "obtainable from" as used herein means that the saponin(s) can be obtained from the plant, isolated from the plant, or obtained from an alternative source, such as by chemical synthesis or enzymatic production. In contrast, the term "obtained" as used herein means that the saponin(s) are derived directly from the plant. For example, in one embodiment, the saponin(s) may be a "natural extract containing saponin(s)." The at least one saponin may be of natural or synthetic origin.

[0085] "Purified saponin(s)" means one or more saponins of natural or synthetic origin having a concentration of at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 99.9% of one or more saponins as defined above (such as Quillaja saponin(s) and / or Yucca saponin(s)).

[0086] By "saponin(s) containing extract" is meant any natural extract containing at least one type of saponin as defined above, which may be derived from, for example but not limited to, soybean, bean, pea, oat, solanum and allium species, tomato, asparagus, tea, peanut, spinach, sugar beet, yam, blackberry, licorice root, primrose root, senega root, Quillaja (such as Quillaja saponaria), Yucca (such as Yucca shidigera), and / or gypsophila.

[0087] According to the present invention, the at least one saponin may be derived from a single source or from multiple sources.

[0088] According to the present invention, the extract containing at least one saponin may be derived from a single source or from multiple sources.

[0089] In one embodiment, the saponin component is a natural extract such as Quillaja extract, tea extract, licorice extract, beetroot extract, sugar beet extract, ginseng extract, oat extract, yucca extract, or a mixture thereof, having at least 5% wt / wt, or at least 10% wt / wt, or at least 15% wt / wt, or at least 20% wt / wt, or at least 25% wt / wt, or at least 30% wt / wt, or at least 35% wt / wt, or at least 40% wt / wt, or at least 50% wt / wt, or at least 60% wt / wt, or at least 70% wt / wt, or at least 80% wt / wt of saponin. In one embodiment, the saponin component may be a Quillaja extract having at least 60% saponin, for example, 65% wt / wt.

[0090] In a preferred embodiment, the saponin(s) is Quillaja. As used herein, the term "Quillaja" includes one or more purified Quillaja saponins of natural or synthetic origin, as well as extracts obtained or obtainable from Quillaja.

[0091] The saponin(s) (such as Quillaja saponin) of the compositions of the present invention may be present in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.8%, 2%, 2.5%, 3%, 3.5%, 4%, or 5% by weight of the composition. may be present in an amount of 4.5% to about 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2.4%, 2.3%, 2.2%, 2%, 1.5%, 1%, 0.8%, 0.6%, 0.5%, or up to 0.2% by weight, for example, about 0.4% to about 3% by weight of the composition, for example, 0.5% to about 2.5% or about 0.65% or about 2% by weight. In a preferred embodiment, the one or more saponin(s) is one or more Quillaja saponin(s). In one embodiment, the Quillaja saponin is purified Quillaja saponin. In a more preferred embodiment, the one or more saponins may be provided as an extract obtained or obtainable from the Quillaja genus.

[0092] In the present invention, "purified Quillaja saponin" may refer to one or more Quillaja saponins of natural or synthetic origin that have a purity of at least 80%, such as at least 90%, for example at least 95%, for example at least 99%.

[0093] The saponin(s) used in the process of the present invention (such as purified Quillaja saponin(s) or Quillaja extracts containing saponin(s) or from or obtainable therefrom) can be in any form, such as a liquid or a solid. For example, the saponin(s) can be used in the form of a solid, such as a powder.

[0094] The Quillaja saponin(s) (such as purified Quillaja saponin or an extract from or obtainable from the Quillaja genus containing saponin(s)) used in the process of the present invention may be in any form, such as a liquid or a solid. For example, the Quillaja extract may be used in the form of a solid, such as a powder.

[0095] When saponin(s) (such as Quillaja saponin) are present in the compositions of the present invention, other solvents such as water and / or alcohol may be added to the solid or liquid saponin(s) (such as Quillaja saponin).

[0096] In a preferred embodiment, the one or more saponins are Quillaja saponin(s) and are present in the final composition at about 0.5% to about 5%, such as about 0.8 to about 2%, for example about 1% to 1.5%, for example about 1.3% wt / wt.

[0097] In the methods or uses described herein, the composition may optionally comprise vegetable oil.For example, the composition of the present invention may comprise vegetable and / or vegetable oil selected from the group consisting of coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, rapeseed oil including canola oil, safflower oil, sesame oil, soybean oil, sunflower oil, and mixtures thereof.

[0098] The vegetable oil present in the compositions of the present invention may be present in an amount of from about 1% to about 20% by weight of the composition, such as from about 2.5% to about 10% or about 5% vegetable oil.

[0099] In a preferred embodiment of the compositions, methods or uses described herein, the composition comprises about 30 to about 40% ethanolic turmeric rhizome extract (having at least 80%, e.g., at least 90%, curcuminoids), about 55 to about 65% acacia gum, about 3 to about 7% sunflower oil, and about 1 to about 3% quillaja extract.

[0100] Unless otherwise stated herein, the weight percentages stated are based on the total weight of the resulting (dry) composition.

[0101] In the methods or uses described herein, the composition comprising curcuminoids may be provided in the form of a (suitable) composition, such as a "pharmaceutical composition" or a "food composition".

[0102] In certain embodiments, the composition comprising the curcuminoid may be provided in the form of a pharmaceutical composition (which may also be referred to as a pharmaceutical formulation or a veterinary composition) or a nutraceutical composition comprising the curcuminoid and optionally pharmaceutically acceptable excipients or (functional) food acceptable ingredients, as appropriate.

[0103] "Functional food composition," as used herein, refers to a nutraceutical composition, functional food composition, dietary or food product or dietary supplement for humans or animals (e.g., a nutraceutical composition, i.e., a drink, feed or pet food or a food, drink, feed or pet food supplement). The nutraceutical composition can be presented as a beverage, dairy product, bakery product, etc.

[0104] When used in functional foods such as beverages, dairy products, bakery products, etc., the compositions of the present invention are incorporated into the food product (e.g., in liquid or solid form) to provide an effective amount of curcuminoids (e.g., at least 90 mg of curcuminoids).

[0105] As used herein, references to pharmaceutically (or veterinarily) acceptable excipients may refer to pharmaceutically (or veterinarily) acceptable adjuvants, diluents, and / or carriers, as known to those skilled in the art.

[0106] Food-acceptable ingredients include those known in the art (including those also referred to herein as pharmaceutically acceptable excipients) and may be natural or non-natural, i.e., their structure may or may not occur in nature. In some cases, they may be derived from naturally occurring compounds or subsequently modified (e.g., maltodextrin).

[0107] By "pharmaceutically acceptable" (or veterinarily acceptable), we mean that the additional components of the composition are sterile and pyrogen-free. Such components must be "acceptable" in the sense of being compatible with the extract of the present invention and not harmful to the recipient thereof. Thus, "pharmaceutically acceptable" includes any compound(s) used in forming part of a formulation that is intended to act merely as an excipient, i.e., not intended to have biological activity itself. Thus, pharmaceutically acceptable excipients are generally safe, non-toxic, and not biologically undesirable or otherwise undesirable. Those skilled in the art will understand that the extracts of the present invention (e.g., in the form of compositions such as pharmaceutical compositions as described herein and known to those skilled in the art) may be administered to a patient or subject (e.g., a human or animal patient or subject) by any suitable route, such as oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal, intraperitoneal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes. In particular, the extracts of the present invention may be administered orally. In such cases, pharmaceutical compositions according to the present invention may be specifically formulated for administration by the oral route. Suitable pharmaceutical (or veterinary) carriers include inert solid diluents or fillers, sterile aqueous solutions, and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, maltodextrin, talc, gelatin, silica, agar, pectin, acacia, magnesium stearate, stearic acid, gum arabic, modified starch, and lower alkyl ethers of cellulose. Examples of liquid carriers are molasses, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene, and water. Additionally, the carrier or diluent may include any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

[0108] Pharmaceutical (or veterinary) compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules. Where appropriate, they may be prepared with coatings, such as enteric coatings, or they may be formulated to provide controlled release of the active ingredient, such as sustained or extended release, according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily suspensions, syrups and elixirs.

[0109] Compositions described herein (e.g., pharmaceutical or food compositions), such as those intended for oral administration, may be prepared according to methods known to those skilled in the art, for example by mixing the components of the composition.

[0110] Such compositions as described herein may contain one or more additional components selected from the group consisting of food ingredients such as sweeteners, flavoring agents, coloring agents, and preservatives. Tablets may contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients (or ingredients) suitable for the manufacture of tablets. These excipients (or ingredients) may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch, maltodextrin, or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used.

[0111] In preferred embodiments, the composition is formulated to provide a single dose of curcuminoid in an amount of about 50 mg / dose, about 60 mg / dose, 70 mg / dose, 80 mg / dose, 90 mg / dose, 100 mg / dose, 150 mg / dose, 200 mg / dose, 300 mg / dose, to about 1400 mg / dose, 1300 mg / dose, 1200 mg / dose, 1100 mg / dose, 1000 mg / dose, 900 mg / dose, 800 mg / dose, 700 mg / dose, 600 mg / dose, 500 mg / dose, 400 mg / dose, e.g., about 70 mg / dose to about 100 mg / dose, e.g., about 90 mg / dose.

[0112] In a preferred embodiment of the methods / uses described herein, the composition may be formulated and / or administered as a single dose formulation.For example, the composition may be formulated as a single dose (e.g., a 300 mg formulation) having a curcuminoid content of at least 90 mg.

[0113] Furthermore, due to the very high efficacy of the compositions of the present invention, the dosage (e.g., daily dose) of curcuminoids can also be reduced.

[0114] In the methods / uses described herein, the compositions may be administered or used to provide curcuminoids in an amount of about 50 mg / day, about 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 300 mg / day to about 1400 mg / day, 1300 mg / day, 1200 mg / day, 1100 mg / day, 1000 mg / day, 900 mg / day, 800 mg / day, 700 mg / day, 600 mg / day, 500 mg / day, 400 mg / day, e.g., about 70 mg / day to about 100 mg / day, e.g., about 90 mg / day. For example, the compositions may be formulated as a single dose (e.g., 300 mg) having a curcuminoid content of at least 90 mg / day.

[0115] For example, the composition may provide curcuminoids in an amount of about 1 to about 10 mg per kg of body weight, such as about 2.5 to about 7.5 mg per kg of body weight, such as about 5 mg per kg of body weight, or such as about 1.29 mg per kg of body weight (90 mg of curcuminoids for a 70 kg body weight).

[0116] In a preferred embodiment, the dosage is 300 mg, and the daily dose of curcuminoid is about 70 mg / day to about 150 mg / day of curcuminoid, for example, about 70 mg / day to about 100 mg / day of curcuminoid, for example, about 90 mg / day of curcuminoid.

[0117] The timing and duration of administration of the compositions of the present invention can vary, for example, the composition may be administered or used before a food containing fat.

[0118] In certain embodiments of the compositions, uses, or methods for use of the present invention, the composition is administered or used at least two days before a fat-containing food is ingested or administered to a subject, or at least one day before a fat-containing food is ingested or administered, or several hours before a fat-containing food, and may optionally be administered one day after the fat-containing food.

[0119] Fat-containing foods are considered to be foods that contain at least 10%, at least 20%, at least 30% w / w fat.

[0120] In one embodiment of the present invention, the method of delivery is oral administration in the form of a liquid, solid, or paste.Solid dosage forms for oral administration may include capsules, tablets, caplets, pills, troches, chewable tablets, lozenges, powders, and granules.Capsules typically comprise a core material containing the composition of the present invention and a shell encapsulating the core material.The core material may be a solid, liquid, or emulsion.The shell material may comprise soft gelatin, hard gelatin, or a polymer. Suitable polymers include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose (HPMC), methylcellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate and sodium carboxymethylcellulose; acrylic acid polymers and copolymers, preferably those formed from acrylic acid, methacrylic acid, methyl acrylate, ammoniomethyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate (for example, copolymers sold under the trade name "Eudragit"); vinyl polymers and copolymers such as polyvinylpyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, vinyl acetate-crotonic acid copolymer, and ethylene-vinyl acetate copolymer; and shellac (purified lac). Some such polymers can also function as taste masking agents.

[0121] Tablets, pills, and the like may be compressed, multi-compressed, multi-layered, and / or coated. The coating may be single or multiple. In one embodiment, the coating material may comprise a polysaccharide extracted from a plant, fungus, or microorganism, or a mixture of sugars and glycoproteins. Non-limiting examples include corn starch, wheat starch, potato starch, tapioca starch, cellulose, hemicellulose, dextran, maltodextrin, cyclodextrin, insulin, pectin, mannan, gum arabic, locust bean gum, mesquite gum, guar gum, karaya gum, ghatti gum, tragacanth gum, funori, carrageenan, agar, alginate, chitosan, or gellan gum. In another embodiment, the coating material may comprise a protein. Suitable proteins include, but are not limited to, gelatin, casein, collagen, whey protein, soy protein, rice protein, and corn protein. In an alternative embodiment, the coating material may comprise a fat or oil, particularly a high-melting fat or oil. The fat or oil may be hydrogenated or partially hydrogenated, and is preferably derived from a plant. The fat or oil may comprise a glyceride, a free fatty acid, a fatty acid ester, or a mixture thereof. In yet another example, the coating material may comprise an edible wax. The edible wax may be derived from an animal, insect, or plant. Non-limiting examples include beeswax, lanolin, bayberry wax, carnauba wax, and rice bran wax. Tablets and pills may further be prepared with an enteric coating.

[0122] For example, if the final product is a beverage, the compositions of the present invention may be added to the final product to obtain a final dose of curcuminoids of about 70, 80, 90, 100, 150, 200, 250 mg / day to about 1000, 900, 850, 800, 750, 700, 650, 600, 550, 500, 450, 400, 350, 300 mg / day, e.g., about 70 mg / day to about 150 mg / day, e.g., about 70 mg / day to about 90 mg / day. For example, the composition may provide curcuminoids in an amount of about 1 to about 10 mg / kg body weight, e.g., about 2.5 to about 7.5 mg / kg body weight, or about 5 mg / kg body weight, e.g., about 1.29 mg / kg body weight (90 mg of curcuminoids for a 70 kg body weight).

[0123] Alternatively, powders or granules embodying the compositions disclosed herein may be incorporated into food products. In a preferred embodiment, the food product may be a drink for oral administration. Non-limiting examples of suitable drinks include fruit juices, fruit drinks, artificially flavored drinks, artificially sweetened drinks, carbonated drinks, sports drinks, liquid dairy products, shakes, etc., to which excipients may also be added. Other suitable means for oral administration include aqueous or non-aqueous solutions, emulsions, suspensions, and solutions and / or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, colorants, and flavoring agents. Furthermore, chewable forms may be used, as disclosed in U.S. Patent No. 7,223,417, which is incorporated herein by reference in its entirety.

[0124] The beverage products disclosed herein optionally contain a flavor composition, i.e., one or more flavor components, such as natural or synthetic fruit flavors, botanical flavors, other flavors, and mixtures of any of these. As used herein, the term "fruit flavor" generally refers to flavors derived from the edible reproductive parts of seed plants. Included are both those with sweet pulp associated with the seed, such as bananas, tomatoes, cranberries, and those with small, fleshy berries. The term "berry" is also used herein to include aggregate fruits, i.e., those that are not "true" berries but are generally accepted as berries. Also included within the term "fruit flavor" are synthetically prepared flavors designed to mimic fruit flavors derived from natural sources. Examples of suitable fruit or berry sources include whole berries or parts thereof, berry juice, berry juice concentrate, berry puree and blends thereof, dried berry powder, dried berry juice powder, and the like.

[0125] The composition may be a solid foodstuff. Suitable examples of solid foodstuffs include food bars, gummies, snack bars, cookies, brownies, muffins, crackers, chewable gum, ice cream bars, frozen yogurt bars, chewy snacks, etc. In one embodiment, the method comprises administering the composition as described above multiple times per day, or, if taken as a liquid, may be mixed and taken throughout the day.

[0126] In an alternative or further embodiment of the method of delivery, the composition may also be used in conjunction with exercise. For example, the composition may be administered before, during, or immediately after exercise. In such an embodiment, the composition may be in the form of, for example, a sports drink.

[0127] Typically, the period of administration of the composition of the present invention comprising a curcuminoid (such as a pharmaceutical or food composition comprising a curcuminoid), in use in the methods of the present invention described herein, is longer than 2 days, longer than 3 days, longer than 4 days, longer than 5 days, longer than 6 days, longer than 7 days; longer than 1 week, longer than 2 weeks, longer than 3 weeks, longer than 4 weeks, longer than 5 weeks, longer than 6 weeks, longer than 7 weeks, longer than 8 weeks, longer than 9 weeks, longer than 10 weeks, longer than 1 month, longer than 1 month, longer than 2 months, longer than 3 months, longer than 4 months, longer than 5 months, longer than 6 months, longer than 7 months, longer than 8 months, longer than 9 months, longer than 10 months ...1 months, longer than 12 months.

[0128] "Subject" refers to a human or an animal, including, but not limited to, a mouse, rat, rabbit, dog, cat, pig, cow, and non-human primate, including, but not limited to, a monkey and chimpanzee. In a preferred embodiment, the subject is a human (female or male).

[0129] "Administration" or "administering" refers to the route by which a compound or composition provided herein is introduced into an individual to perform its intended function. Examples of routes of administration that can be used include, but are not limited to, oral and parenteral administration, such as subcutaneous, intravenous, or intramuscular injection or infusion.

[0130] A "healthy subject" refers to an individual who is not known to suffer from any significant disease and who represents the general population.

[0131] As used herein, the term "treatment" (and, similarly, "treating") takes its ordinary meaning in the medical field. In particular, the term can refer to achieving a reduction in the severity (e.g., at least a 10% reduction, e.g., at least a 20%, 30%, or 40% reduction, e.g., at least a 50% reduction) of one or more clinical symptoms associated with a disease or disorder (e.g., endotoxemia or leaky gut syndrome), which may be determined using techniques known to those of skill in the art (e.g., by a physician) or those described in the examples), and / or delaying the progression of the disease or disorder (i.e., increasing the amount of time it takes for the disease or disorder to progress to a more severe state, e.g., as compared to the time expected to take in a patient not so treated). As used herein, the term "prevention" (and, similarly, "preventing") includes reference to prophylaxis of a disease or disorder (and vice versa). In particular, the term can refer to achieving a reduction (e.g., at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g., at least a 50% reduction) in the likelihood that a patient (or healthy subject) will develop a condition.

[0132] As used herein in connection with a medical condition, the term "reducing" can refer to making the observed amount smaller or decreasing in size (i.e., lowering the level of LPS in the blood). In particular, the term can refer to achieving a reduction (e.g., at least a 10% reduction, e.g., at least a 20%, 30%, or 40% reduction, e.g., at least a 50% reduction) in the likelihood that a patient (or healthy subject) will develop a condition.

[0133] To measure a decrease in blood LPS levels or a decrease in blood ApoB48 levels, the amount or concentration of LPS may be measured and then compared to a cut-off value established in a reference population. The phrase "comparing the LPS value to a cut-off value established in a reference population" is merely used to further express what will be apparent to those skilled in the art.

[0134] In one embodiment of the present invention, a control value is established using a control sample obtained from an individual, or preferably from a control population (also called a reference population) of individuals known to be free of a particular condition, i.e., low LPS or low Apo48 blood levels. Alternatively, a control value is defined based on an analysis of a population of individuals known to have a particular condition (e.g., elevated LPS or elevated blood ApoB48 levels). Here, the control value must be selected to be below the value typically determined for this population. Finally, a control value can be obtained by evaluating a healthy population (low LPS or ApoB48 values) and a diseased population (elevated LPS or ApoB48 values) and establishing a cutoff value to define the percentage decrease in the value (blood LPS or Apo48) compared to the control population. Selecting an appropriate control sample / population and / or control value for the marker established therein is within the skill of the practitioner.

[0135] Those skilled in the art will appreciate that the absolute marker value established in a control depends on the assay used. Preferably, samples from 100 or more well-characterized individuals from an appropriate control / reference population are used to establish the control value. It is also preferred that the control / reference population be selected to consist of at least 20, 30, 50, 200, 500, or 1000 individuals. Healthy individuals represent a preferred reference population for establishing a control value.

[0136] The treatment or relief achieved by the compositions of the present invention may be achieved 24 hours after oral ingestion, or 48 hours, 72 hours, 4 days, 5 days, or 1 week after ingestion of the compositions of the present invention.

[0137] For the avoidance of doubt, any preference, option, specific feature, etc. for a given aspect, feature or parameter of the invention should be deemed to be disclosed in combination with any and all other preferences, options, specific features, etc. as indicated for the same or other aspects, features and parameters of the invention, unless the context indicates otherwise. As used herein, the term "about," when referring to a measurable value (such as the amount or weight of a specific component in a reaction mixture), refers to a variation of ±20%, ±10%, ±5%, ±1%, ±0.5%, or specifically ±0.1% relative to the specified amount. For example, a variation of ±0.5% relative to the percentage of a component in a composition of the invention means a variation of 0.5% relative to the given percentage, i.e., ±0.5% of 10% means a variation of 9.5% to 10.5%. [Example]

[0138] 1. Test formulation The test formulation (TPG) consisted of a natural powder extract obtained from turmeric (Curcuma longa) root, acacia gum, sunflower oil, and quillaja extract. It was developed for use as a food supplement. Its safety has already been tested in preclinical and human trials.

[0139] The test formulation consisted of 30-40% ethanol extract of Curcuma longa rhizome, 55-65% acacia gum, 3-7% sunflower oil, and 1-3% quillaja extract. The quillaja extract is an extract powder containing approximately 65% ​​saponins by dry weight. The curcuminoid content was 30% w / w (curcumin 23% w / w, DMC 7% w / w, and BDMC (% w / w of the total weight of the test formulation)). The test formulation was prepared in capsule form.

[0140] Test formulations were selected for in vivo studies of fat-induced intestinal barrier disruption as measured by LPS translocation in IBS patients with diarrhea-dominant subtype (IBS-D). The primary objective of this study was to determine the effect of short-term test formulation (Turmipure GOLD®) supplementation on LPS translocation in IBS-D patients after a high-fat challenge. The secondary objective of this study was to determine the effect of short-term test formulation (Turmipure GOLD®) supplementation on gastrointestinal complaints and LPS-related biomarkers in IBS-D patients after a high-fat challenge.

[0141] This double-blind, randomized, placebo-controlled crossover study included 20 adult (18–70 years) patients with IBS-D. Participants received a single dose (300 mg) of turmeric or a placebo three times. The first study parameter is the blood LPS level, and the second study parameter is the blood level of LPS-related biomarkers. Blood sampling was performed via a cannula.

[0142] 2. Study Design To study the effect of the test formulation on postprandial LPS translocation, a double-blind, randomized, placebo-controlled crossover study was conducted on LPS-related biomarkers and gastrointestinal complaints in IBS-D patients (Figure 3). Before the start of supplementation (day -3), participants answered questions regarding the severity of their IBS-related gastrointestinal complaints (IBS-SSS). Next, participants consumed either a 300 mg capsule of the test formulation or a placebo (colored acacia gum) three times: on days 1, 2, and the morning of the high-fat challenge test. Additionally, they consumed a standardized meal with a high-fat challenge test the day before the test. The two test days were separated by a washout period of at least 14 days. On the test day, participants consumed a high-fat shake, followed by 5-hourly blood draws and a short questionnaire regarding their gastrointestinal complaints.

[0143] 2.1 Population (base) This study included 20 adult patients with IBS-D. This subgroup of IBS patients was selected because they generally have elevated plasma LPS levels, which have been shown to indicate impaired intestinal barrier function and low-grade inflammation. They also demonstrated a greater frequency of gastrointestinal complaints after consuming a high-fat diet. Therefore, intervention may be particularly beneficial for this subgroup. Because increased BMI is known to have beneficial effects on intestinal barrier function and low-grade inflammation, a slightly higher upper BMI range was applied for inclusion.

[0144] 2.2 Study patient inclusion criteria To be eligible to participate in this study, subjects must meet all of the following criteria: - Patients with IBS who fulfilled the Rome IV criteria plus additional criteria specific to the diarrhea-predominant subtype, based on the most frequently self-reported stool type using the Bristol Stool Chart (BSC). - Adult men and women aged 18 to 70. - Body mass index (BMI) between 18.5 and 30 kg / m2. - Willingness to maintain a stable eating pattern throughout the study period.

[0145] 3. Investigational Product / Treatment Subjects were supplemented with one capsule of the test formulation or placebo daily for three days: 48 hours before, 24 hours before, and on the day of the high-fat challenge test. Capsules containing 300 mg were consumed with water before breakfast (7:00-8:00 hours).

[0146] 4. Main Study Parameters / Endpoints The primary study parameter was LPS translocation, measured as the level of LPS in venous blood samples collected at baseline and every 5 hours after high-fat shake consumption. LPS was determined by Pyrochrome-LAL kit (Associates of Cape Cod Inc.).

[0147] 4.1. Secondary Study Parameters / Endpoints The second set of parameters was gastrointestinal complaints and LPS-related biomarkers in venous blood samples collected at baseline and every 5 hours after ingestion of the high-fat shake.

[0148] Gastrointestinal complaints were measured by repeated short questionnaires (T = 1, 2, 3, 4, 5 hours). Abdominal pain, bloating, distension, nausea, heartburn LPS-related biomarkers: ApoB48 concentrations were assessed using a commercially available sandwich ELISA (Fujifilm Wako Shibayagi Co., Ltd.). LBP was measured by a commercially available ELISA assay (Sanbio BV). sCD14 was measured using a commercially available ELISA assay (Sanbio BV). All laboratory analyses were performed at the Wageningen Food & Biobased Research laboratory facilities.

[0149] 4.2. Randomization, blinding, and treatment assignment Study participants were randomized across two crossover arms (test drug → placebo and placebo → test drug). Block randomization for BMI and age was applied. Subjects were sorted by BMI and age to ensure similar BMI and age in both treatment groups, and for each block of two participants, two possible treatment sequences (1 → 2 and 2 → 1) were randomly assigned.

[0150] Other clinically relevant differences in baseline characteristics were considered in the statistical analysis (analysis of covariance).

[0151] Both capsules were uniformly packaged but with coded labels specifically corresponding to the intervention, i.e., ensuring double-blinding. After analysis of all data, the product coding was unblinded for the investigators.

[0152] Baseline IBS complaints and daily questions On day -3, subjects completed the online IBS-SSS questionnaire. From day -3 to day +2, subjects completed a short questionnaire once daily via an app (LifeData, LLC) inquiring about, among other things, GI complaints and supplement compliance, when applicable.

[0153] Supplement intake Subjects took one capsule (with water) on Days -2 and -1 before breakfast in the morning between 7:00 and 8:00 AM (supplement or placebo), and on the morning of the test day at the research unit. After at least 14 days of washout and crossover, subjects took one capsule (with water) on Days -2 and -1 before breakfast in the morning between 7:00 and 8:00 AM (supplement or placebo), and again on the morning of the second test day at the research unit.

[0154] Test date ("Day 0") Subjects consumed a standardized low-fat dinner before the test day and were asked to abstain from alcohol and strenuous exercise. After an overnight fast, all subjects traveled to the research facility by their own transportation. Subjects consumed their third and final supplement capsule (T = -1 h). A research nurse inserted a cannula to allow blood collection throughout the day. A baseline (t = 0) blood sample was then collected. After the baseline measurement, participants consumed a high-fat shake within 10 minutes (T = 0). After the shake consumption, postprandial blood samples were collected via the cannula every 5 hours. At each collection, 11 mL of blood was drawn through the cannula (4 mL EDTA plasma, 4 mL serum, and 3 mL dummy blood to flush the cannula), for a total blood volume of 66 mL per test day.

[0155] Statistical analysis was performed using SPSS statistics. A p-value of p<0.05 was considered statistically significant. Continuous data are generally presented as mean ± standard deviation (SD). Data may be log-transformed to normalize data distribution before parametric statistical analysis.

[0156] result: As seen in Figure 1, a trend was found for the baseline effect of the test formulation (Supplement A) on LPS levels (p=0.06).

[0157] As can be seen in Figure 2, a significant effect of the test formulation (Supplement A) was found on postprandial levels of ApoB48 (p<0.001), with lower concentrations of ApoB48 observed at 2, 3, 4, and 5 hours after the high-fat challenge. A significantly lower area under the concentration-time curve (ApoB48 AUC) was also observed (p=0.04).

Claims

1. A composition comprising i) a curcuminoid, ii) modified starch and / or acacia gum, and iii) one or more saponins for use in reducing blood LPS levels, reducing endotoxemia, maintaining the intestinal barrier and / or treating, reducing and / or preventing leaky gut syndrome.

2. A composition comprising i) a curcuminoid, ii) modified starch and / or acacia gum, and iii) one or more saponins for use in reducing intestinal lipid absorption, reducing blood ApoB48 levels, and / or treating, reducing and / or preventing dyslipidemia.

3. Use of a composition comprising i) a curcuminoid, ii) a modified starch and / or acacia gum, and iii) one or more saponins for use in reducing blood LPS levels, reducing endotoxemia, maintaining the intestinal barrier, and / or treating, reducing, and / or preventing leaky gut syndrome.

4. Use of a composition comprising i) a curcuminoid, ii) modified starch and / or acacia gum, and iii) one or more saponins for reducing intestinal lipid absorption, reducing blood ApoB48 levels, and / or treating, reducing, and / or preventing dyslipidemia.

5. A method for maintaining liver and / or cardiovascular health comprising administering to a subject in need thereof an effective amount of a composition comprising: 1) a curcuminoid, 2) a modified starch and / or acacia gum, and 3) one or more saponins.

6. 6. The composition for use, use, or method of any one of claims 1 to 5, wherein the composition comprising curcuminoid is administered or used to provide curcuminoid in an amount of about 50 mg / dose to about 300 mg / dose, such as about 60 mg / dose, 70 mg / dose, 80 mg / dose, 90 mg / dose, 100 mg / dose, 150 mg / dose, 200 mg / dose, or 300 mg / dose.

7. 7. The composition for use, use or method according to any one of claims 1 to 6, wherein the curcuminoid is curcumin and its phase 1 or phase 2 metabolites, demethoxycurcumin and its phase 1 or phase 2 metabolites, bisdemethoxycurcumin and its phase 1 or phase 2 metabolites and mixtures thereof.

8. 8. The composition, use, or method for use according to claim 7, wherein the curcuminoid is selected from curcumin, demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), and mixtures thereof.

9. 9. The composition, use, or method for use according to any one of claims 1 to 8, wherein the composition comprises curcuminoid in an amount of from 30mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, or 90mg to about 1500mg, 1400mg, 1200mg, 1110mg, 1000mg, 900mg, 800mg, 700mg, 600mg, 500mg, 400mg, 300mg, 250mg, 200mg, 150mg, 100mg, or 95mg, such as from about 70mg to about 300mg, or from about 70mg to about 200mg, from about 70mg to about 100mg, such as 90mg.

10. 10. The composition, use, or method for use according to any one of claims 1 to 9, wherein the gum acacia is in an amount from about 30%, 35%, 40%, 45%, 50%, 55% to about 85%, 80%, 75%, 70%, 65%, 60% by weight of the composition, such as from about 50% to about 60% by weight of the composition, or up to about 58% by weight of the composition, based on the total weight of the composition.

11. 11. The composition, use, or method for use according to any one of claims 1 to 10, wherein the one or more saponins are selected from Quillaja saponin, Yucca saponin, tea saponin, peanut saponin, spinach saponin, sugar beet saponin, yam saponin, blackberry saponin, licorice root saponin, primula root saponin, ginseng saponin, and mixtures thereof.

12. 12. A composition, use, or method for use according to any one of claims 1 to 11, wherein the at least one saponin is present in an amount of from about 0.1% to about 5% by weight of the composition, such as from about 0.5% to about 3% w / w by weight of the composition, or up to about 1.3% by weight, based on the total weight of the composition.

13. 13. The composition, use, or method for use according to any one of claims 1 to 12, wherein the composition comprises particles having an average diameter of from about 100 nm to about 10,000 nm, such as from about 100 nm to about 700 nm, or from about 1,000 nm to about 6,000 nm, as measured using laser diffraction.

14. 14. The composition for use, use or method of any one of claims 1 to 13, wherein the composition is administered or used to provide curcuminoids in an amount of about 50 mg / day, about 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 100 mg / day, 150 mg / day, 200 mg / day, 300 mg / day, to about 1400 mg / day, 1,300 mg / day, 1,200 mg / day, 1,100 mg / day, 1,000 mg / day, 900 mg / day, 800 mg / day, 700 mg / day, 600 mg / day, 500 mg / day, 400 mg / day, such as about 70 mg / day, to about 100 mg / day, such as about 90 mg / day.

15. 15. The composition, use or method for use according to any one of claims 1 to 14, wherein the composition is administered or dosed in a dosage of about 100 mg to about 500 mg, such as about 300 mg, and the daily dosage of the curcuminoid is about 50 mg / day to about 500 mg / day, such as about 70 mg to about 90 mg.

16. 16. The composition, use, or method for use of claim 15, wherein the composition is administered or used to provide curcuminoids in an amount of about 70 mg / day to about 90 mg / day of curcuminoids, together with about 54 mg / day to about 69 mg / day of curcumin, and about 16 mg / day to about 21 mg / day of DMC and BDMC.

17. 17. The composition, use or method for use according to any one of claims 1 to 16, wherein the composition is administered or used once daily.

18. 18. A composition for use, use or method according to any one of claims 1 to 17, wherein the composition is administered or used before a food containing fat is eaten by a subject.

19. 19. A composition for use, use or method according to any one of claims 1 to 18, wherein the composition is administered or used e.g. at least one day before the food comprising fat is eaten by the subject, e.g. at least two days before the food comprising fat is eaten by the subject, such as several hours before the food comprising fat is eaten by the subject, and optionally also one day after the food comprising fat is eaten by the subject.

20. A composition for use, use or method according to any one of claims 1 to 19, wherein the composition is indicated as a pharmaceutical, nutritional or food composition.

21. A composition for use, a use or a method according to any one of claims 1 to 20, wherein the subject is a human.

22. 22. The composition for use, use or method according to any one of claims 1 to 21, wherein the subject is suffering from IBS.

Images