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1. WO2017196632 - ADDITIVE FOR A NUTRITIONAL COMPOSITION

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

ADDITIVE FOR A NUTRITIONAL COMPOSITION

FIELD OF THE INVENTION

The present invention is directed to a curcuminoid additive for a nutritional composition. The additive has been found to provide improved curcuminoid solubility in water. The invention is also directed to a nutritional composition comprising the additive and methods of preparing the additive and the nutritional composition.

BACKGROUND

Curcuminoids have been suggested for a variety of therapeutic and prophylactic applications. However, many curcuminoids have poor bioavailability when administered orally. This is thought to be due in part to their poor aqueous solubility.

Tetrahydrocurcumin (THC) in particular is known to be difficult to solubilise in water, which is also the limiting factor for its absorption in the body (Setthacheewakul et al., AAPS PharmaSciTech, Vol. 12, No. 1 , March 201 1 ).

Setthacheewakul et al. discloses a self-emulsifying floating drug delivery system (SEFDDS) for improving the solubility, dissolution and controlled release of THC.

However, this system is a pharmaceutical rather than nutritional composition and it relies on components that are not food grade materials.

Food grade additives that are intended to improve the solubility of curcuminoids have been prepared previously. For example, WO 2012/049253 discloses a solid dispersion formulation comprising one or more curcuminoids, a nutritionally acceptable

thermoplastic polymer and a phosphatide. The curcuminoid is homogeneously dispersed in the matrix of the solid dispersion product, thus improving its solubility. These additives are useful in nutritional formulations where enhanced curcuminoid solubility is desired.

However, there remains within the nutritional field a need to provide curcuminoid formulations which increase the aqueous solubility of the curcuminoid and/or provide optimum bioavailability of the curcuminoid when administered orally.

Accordingly, it is one object of the present invention to provide a curcuminoid additive or a nutritional composition having enhanced curcuminoid aqueous solubility relative to the curcuminoid alone.

It is an alternative and/or additional object to provide a curcuminoid additive or a nutritional composition having enhanced curcuminoid aqueous solubility relative to existing curcuminoid-solubilising systems.

It is an alternative and/or additional object to provide a curcuminoid additive or a nutritional composition providing improved oral bioavailability of the curcuminoid relative to existing curcuminoid formulations.

SUMMARY OF INVENTION

It has been discovered that by combining a curcuminoid with one or more phosphatides and one or more dextrins having a dextrose equivalent of from 6 to 33 to form an additive, the aqueous solubility of the curcuminoid is significantly increased.

Surprisingly, the inventors have found that the effect is far greater when the

aforementioned dextrins are used compared to other polysaccharides. The additive is useful as an enhanced solubility curcuminoid ingredient in nutritional compositions.

Advantageously, the curcuminoid solubilisation is achieved using food grade materials.

Accordingly, in a first aspect, the present invention provides an additive for a nutritional composition, the additive comprising:

(i) one or more curcuminoids;

(ii) one or more phosphatides; and

(iii) one or more dextrins having a dextrose equivalent of from 6 to 33.

In a second aspect, the present invention provides a nutritional composition comprising the additive described herein.

In a third aspect, the present invention provides a nutritional composition as described herein for use in a method of treatment of a subject by therapy.

In a fourth aspect, the present invention provides an aqueous non-covalent complex comprising:

(i) one or more curcuminoids;

(ii) one or more phosphatides; and

(iii) one or more dextrins having a dextrose equivalent of from 6 to 33.

In a fifth aspect, the present invention provides a method of preparing an additive for a nutritional composition, the method comprising:

(a) blending one or more curcuminoids, one or more phosphatides, and one or more dextrins having a dextrose equivalent of from 6 to 33 to form a blend;

(b) heating the blend to form a homogeneous melt;

(c) forcing the homogeneous melt through one or more nozzles to form an extrudate; and

(d) cooling the extrudate to form an additive in the form of a solid dispersion product.

In a sixth aspect, the present invention provides a method of preparing a nutritional composition, the method comprising:

(a) forming an additive according to the method as described herein, or providing an additive as described herein; and

(b) mixing the additive with at least one of a protein, a carbohydrate and a fat to form a nutritional composition.

In a seventh aspect, the present invention provides a method of preparing an additive for a nutritional composition, the method comprising dry blending one or more curcuminoids, one or more phosphatides, and one or more dextrins having a dextrose equivalent of from 6 to 33 to form an additive in the form of a dry blend.

In an eighth aspect, the present invention provides a method of preparing a nutritional composition, the method comprising:

(a) forming an additive according to a method as described herein, or providing an additive as described herein; and

(b) mixing the additive with at least one of a protein, a carbohydrate and a fat to form a nutritional composition.

In a ninth aspect, the present invention provides the use of a combination of one or more phosphatides and one or more dextrins having a dextrose equivalent of from 6 to 33 as an aqueous solubility enhancer for a curcuminoid.

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 shows the solubility (in μg/mL) of THC in additives in accordance with the invention compared with a THC control. The Figure also shows the effect of THC loading and lecithin hydrophilicity on THC solubility.

DETAILED DESCRIPTION

A. Definitions

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by the ordinary person skilled in the art to which the invention pertains. Without limiting any term, further clarifications of some of the terms used herein are provided below.

The terms "nutritional composition" as used herein refers to nutritional liquids, nutritional solids, nutritional semi-liquids, nutritional semi-solids, nutritional powders, nutritional supplements, and any other nutritional food product as known in the art. The nutritional powders may be reconstituted to form a nutritional liquid, all of which comprise one or more of fat, protein and carbohydrate, and are suitable for oral consumption by a human.

The term "nutritional liquid" as used herein refers to nutritional products in ready-to-drink liquid form, concentrated form, and nutritional liquids made by reconstituting the nutritional powders described herein prior to use.

The term "nutritional powder" as used herein refers to nutritional products in flowable or scoopable form that can be reconstituted with water or another aqueous liquid prior to consumption and includes both spray dried and dry-mixed/dry-blended powders.

The term "nutritional semi-solid," as used herein, refers to nutritional products that are intermediate in properties, such as rigidity, between solids and liquids. Some semisolids examples include puddings, gelatins, and doughs.

The term "nutritional semi-liquid" as used herein refers to nutritional products that are intermediate in properties, such as flow properties, between liquids and solids. Some semi-liquids examples include thick shakes and liquid gels.

The terms "retort" and "retort sterilized" are used interchangeably herein refer to the common practice of filling a container, most typically a metal can or other similar package, with a nutritional liquid and then subjecting the liquid-filled package to the necessary heat sterilization step, to form a retort sterilized nutritional liquid product.

The terms "aseptic" and "aseptic sterilized" are used interchangeably herein refer to the manufacture of a packaged product without reliance upon the above-described retort packaging step, wherein the nutritional liquid and package are sterilized separately prior to filling, and then are combined under sterilized or aseptic processing conditions to form a sterilized, aseptically packaged, nutritional liquid product.

The terms "administer," "administering," "administered," and "administration," as used herein, should be understood to include providing a nutritional composition to a subject, the act of consuming a nutritional composition (self-administration), and combinations thereof. In addition, it should be understood that the methods disclosed herein may be practised with or without doctor supervision or other medical direction.

The term "subject", as used herein, refers to a mammal, including companion animals, livestock, laboratory animals, working animals, sport animals, and humans. In preferred embodiments, the subject is a human.

The term "additive for a nutritional composition", as used herein, refers to a substance that is added to a nutritional composition in order to supplement it with a particular ingredient. In the context of the present invention, this ingredient is one or more curcuminoids.

All percentages, parts and ratios as used herein, are by dry weight of the additive or nutritional composition, unless otherwise specified. All such weights, as they pertain to listed ingredients, are based on the active level and, therefore, do not include solvents or by-products that may be included in commercially available materials, unless otherwise specified. For example, where the composition is a solid, the percentages are based on the total weight of the additive or nutritional composition prior to reconstitution. Where the composition is a liquid, the percentages are based on the total weight of the additive or nutritional composition minus the solvent, in other words by dry weight of the additive or nutritional composition.

In the following passages different aspects and embodiments of the invention are defined in more detail. Each aspect/embodiment so defined may be freely combined with any other aspect(s) or embodiment(s) unless clearly indicated to the contrary.

B. Additives and nutritional compositions of the invention

In a first aspect, the present invention is directed to an additive for a nutritional composition, the additive comprising:

(i) one or more curcuminoids;

(ii) one or more phosphatides; and

(iii) one or more dextrins having a dextrose equivalent of from 6 to 33.

The term "curcuminoid", as used herein refers to curcumin and derivatives thereof and analogs thereof. These include natural and synthetic derivatives of curcumin. In particular, for the purposes herein, the term "curcuminoid" should be understood to encompass compounds having a 1 ,7-bis (4-hydroxyphenyl)-1 ,6-heptadiene-3,5-dione or 1 ,7-bis(4-hydroxyphenyl)hept-4-en-3-one skeleton wherein the phenyl groups independently may bear one or more alkoxy residues, especially one methoxy residue in 3- position.

Naturally occurring curcuminoids include curcumin (1 ,7-bis-(4-hydroxy-3-methoxyphenyl)-hepta-1 ,6-diene-3,5-dione), desmethoxycurcumin (1 -(4-Hydroxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-hepta-1 ,6-diene-3,5-dione) and bis-desmethoxycurcumin (1 ,7-Bis-(4-hydroxyphenyl)-hepta-1 ,6-diene-3,5-dione). These

compounds can exist in at least two tautomeric forms, keto and enol having the structural formulae


wherein in curcumin and R2 are methoxy, in desmethoxycurcumin is hydrogen and R2 is methoxy, and in bis-desmethoxycurcumin and R2 are hydrogen.

Any suitable source of the curcuminoid can be used, such as the free acid, salts (both organic and inorganic), anhydrous salts, esters (including the methyl ester, ethyl ester, phosphoesters, etc.), lactones and other bioavailable forms of the curcuminoid that are suitable for oral administration.

Exemplary derivatives of curcumin include those having a 1 ,7-bis (4-hydroxyphenyl)-1 ,6-heptane-3,5-dione skeleton wherein the phenyl groups independently may bear one or more alkoxy residues such as tetrahydrocurcumin (1 ,7-bis(4-hydroxy-3-methoxyphenyl)-1 ,6-heptane-3,5-dione). Tetrahydrocurcumin (THC) is also known as white curcumin.

Analogues of curcumin include those derivatives disclosed in U.S. Patent 6,664,272 and Pisano et al., Mol Cancer. 2010, 3; 9(1 ):137, which are herein incorporated by reference.

The term "phosphatide", as used herein, refers to compounds which are derivatives of glycero-3 phosphoric acid that contain at least one O-acyl, O-alkyl or 0-alk-1 '-enyl residue attached to the glycerol moiety and a polar head made of a nitrogenous base, a glycerol, or an inositol unit. The terms "phosphatide", "glycerophospholipid" and "phosphoglyceride" are used interchangeably.

The term "dextrin", as used herein, refers to a carbohydrate produced by the partial hydrolysis of starch. In particular, dextrins are polymers of D-glucose units linked by a-(1→4) or a-(1→6) glycosidic bonds. The one or more dextrins used in the present invention have a dextrose equivalent of from 6 to 33. Dextrose equivalent (DE) is a

measure of the amount of reducing sugars present in a sugar product, relative to dextrose {i.e. glucose), expressed as a percentage on a dry basis. For example, a maltodextrin with a DE of 10 would have 10% of the reducing power of dextrose (which has a DE of 100). Exemplary commercial sources of a suitable dextrin for use herein include corn syrup solids (which typically have a dextrose equivalent of 25).

Curcuminoids are typically poorly soluble or even highly insoluble in water. The present inventors have found that by providing one or more curcuminoids in an additive together with one or more phosphatides and one or more dextrins having a dextrose equivalent of from 6 to 33, the water solubility of the one or more curcuminoids is significantly improved. Phosphatides such as lecithin are known surfactants and, as is shown in the Examples, combining a curcuminoid with phosphatides alone increases the curcuminoid solubility to some extent. Meanwhile, one or more dextrins having a dextrose equivalent of from 6 to 33 alone has very little effect. Surprisingly, the present inventors have found that the effect on curcuminoid solubility of one or more phosphatides and one or more of the aforementioned dextrins in combination is significantly greater than the sum of the individual effects. Thus, the phosphatide(s) and the dextrin(s) interact synergistically to improve the aqueous solubility of the

curcuminoid(s) under like for like dissolution conditions. "Aqueous solubility" or "water solubility" may be measured as the solubility (μς/ηιί) of 0.25 wt% or 0.75 wt% curcuminoid in water at pH 7 and at 25 eC by the method described herein. As a result of this improved aqueous solubility, the bioavailability of the curcuminoid(s) is increased.

Moreover, the inventors have found that dextrins having a dextrose equivalent of from 6 to 33 are significantly more effective than other polysaccharides, such as isomaltulose, which has a dextrose equivalent of 52. This result was unexpected because the water solubility of dextrins having a dextrose equivalent of from 6 to 33 is lower than that of isomaltulose owing to its higher degree of polymerisation (lower dextrose equivalent). In particular, it has previously been reported that the water solubility of curcumin increases in direct proportion with the water solubility of the carrier (Li et al.,

Carbohydrate Polymers, 98, 2013, 1 108-1 1 16).

Because the ingredients of the additive are non-toxic food grade materials, the additive is useful as an enhanced solubility curcuminoid ingredient in nutritional compositions. For example, the additive can be blended with other ingredients to form a nutritional composition. This is advantageous because the majority of prior art curcuminoid solubility enhancers (for example self-emulsifying systems) cannot be used in nutritional compositions because one or more components lack regulatory approval in this field.

It is to be understood that none of components (i)-(iii) are covalently bonded. In other words, the one or more curcuminoids are not covalently bound to the one or more phosphatides or the one or more dextrins having a dextrose equivalent of from 6 to 33, and the one or more phosphatides are not covalently bound to the one or more dextrins having a dextrose equivalent of from 6 to 33.

In certain exemplary embodiments, the one or more curcuminoids are present in a total amount of from about 1 to about 30 wt% by dry weight of the additive, or from about 2 to 25 wt%, or about 5 to 15 wt%, or about 8 to about 12 wt%, or about 10 wt%.

In certain exemplary embodiments, the one or more phosphatides are present in a total amount of from about 1 to about 30 wt% by dry weight of the additive, or from about 2 to 25 wt%, or about 5 to 15 wt%, or about 8 to about 12 wt%, or about 10 wt%.

In certain exemplary embodiments, the one or more dextrins are present in an amount of from about 40 to about 98 wt% by dry weight of the additive, or from about 50 to 96 wt%, or from about 70 to 90 wt%, or from 76 to 84 wt%, or about 80 wt%.

The present inventors have found that the ingredient stability is optimal when working within these ranges.

In certain exemplary embodiments, the one or more curcuminoids and the one or more phosphatides are present in a weight ratio of from about 1 :3 to about 3:1 , or from about 1 :2 to 2:1 , or about 1 :1 . As will be appreciated, these weight ratios refer to the total amount of the one or more curcuminoids and the total amount of the one or more phosphatides.

In certain exemplary embodiments, the one or more curcuminoids and the one or more dextrins are present in a weight ratio of from about 1 :2 to about 1 :20, or from about 1 :4 to about 1 :12, or about 1 :6 to about 1 :10, or about 1 :8. As will be appreciated, these weight ratios refer to the total amount of the one or more curcuminoids and the total amount of the one or more dextrins. It is preferably to include significantly more dextrin in the additive than curcuminoid in order to provide particularly effective curcuminoid solubility enhancement. Moreover, where the additive is in the form of a solid dispersion, the dextrin(s) act as filler in the melt extrusion process and it is beneficial to keep the curcuminoid:dextrin ratio within these ranges for the dextrin(s) to be a particularly effective filler.

In certain exemplary embodiments, the one or more phosphatides and the one or more dextrins are present in a weight ratio of from about 1 :2 to about 1 :20, or from about 1 :4 to about 1 :12, or about 1 :6 to about 1 :10, or about 1 :8. As will be appreciated, these weight ratios refer to the total amount of the one or more phosphatides and the total amount of the one or more dextrins. At these ratios, the synergistic interaction between the one or more phosphatides and the total amount of the one or more dextrins has been found to be strongest.

In certain exemplary embodiments, the one or more curcuminoids, the one or more phosphatides and the one or more dextrins are present in a combined total amount of at least about 90 wt% by dry weight of the additive, or at least about 95 wt%, or at least about 99 wt%, preferably in the aforementioned individual amounts and/or the aforementioned ratios. In certain especially preferred embodiments, the additive consists essentially of or consists of the one or more curcuminoids, the one or more phosphatides and the one or more dextrins, preferably in the aforementioned individual amounts and/or the aforementioned ratios.

In certain exemplary embodiments, the one or more curcuminoids is

tetrahydrocurcumin (THC).

In certain exemplary embodiments, the one or more phosphatides have a hydrophilic-lipophilic balance (HLB) of at least 7.5, or at least 8, or at least 8.5. In certain exemplary embodiments, the one or more phosphatides have a hydrophilic-lipophilic balance

(HLB) of at most 9.5, or at most 9. The HLB is calculated by Griffin's method. The present inventors have found that relatively hydrophilic phosphatides are more effective solubility enhancers than more hydrophobic phosphatides in the context of the present invention.

In certain exemplary embodiments, the one or more phosphatides is a lecithin. The term "lecithin", as used herein, refers to a mixture of phosphatides {e.g.

phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol).

Phosphotidlylcholine is typically the major phosphatide component. Lecithins may also contain other compounds such as free fatty acids, monoglycerides, diglycerides, triglycerides, glycolipids, and other lipid/fatty acid containing compounds. Non-limiting examples of lecithins suitable for use herein include egg lecithin, wheat lecithin, corn lecithin, soy lecithin, modified lecithin, and combinations thereof. In certain preferred embodiments, the lecithin is soy lecithin. Where a lecithin is used, it is again preferred that the lecithin has a hydrophilic-lipophilic balance (HLB) of at least 7.5, or at least 8, or at least 8.5. In certain exemplary embodiments, the lecithin has a hydrophilic-lipophilic balance (HLB) of at most 9.5, or at most 9. It is to be understood that where the one or more phosphatides is a lecithin, the weight percentages and ratios described herein refer to the amount of the lecithin ingredient itself (including any non-phosphatide components present), as opposed to merely the phosphatide component.

Lecithins suitable for use herein may be obtained from any known or otherwise suitable nutrition source. Non-limiting examples include soy lecithin from ADM Specialty Food Ingredients, Decatur, III., USA; soy lecithin from Solae, LLC, St. Louis, Mo., USA; and soy lecithin from American Lecithin Company, Oxford, Conn., USA. The additive has been found to be particularly effective at solubilising the curcuminoid(s) when a lecithin is used as the phosphatide. Without wishing to be bound by theory, it is thought that the maltodextrin may interact with the trimethylammonium head of the phosphatidylcholine and sphingomyelin in the lecithin to form a complex, thus increasing the surface activity of the lecithin.

In certain preferred embodiments, the one or more curcuminoids is THC and the one or more phosphatides is a lecithin.

In certain exemplary embodiments, the one or more dextrins have a dextrose equivalent of from 20 to 30, or from 22 to 28. The present inventors have found that the inclusion of dextrins having a having a dextrose equivalent within these ranges have a significantly greater effect than dextrins having a dextrose equivalent outside these ranges.

In certain exemplary embodiments, the additive comprises less than about 5 wt% additional emulsifier by dry weight of the additive, or less than about 1 wt%, or less than about 0.5 wt%, or 0 wt%. By "additional" it is meant in addition to the one or more curcuminoids, the one or more phosphatides and the one or more dextrins present in the additive. Advantageously, the present additive significantly improves curcuminoid solubility without requiring an additional emulsifier.

In certain exemplary embodiments, the additive comprises less than about 5 wt% water by dry weight of the additive, or less than about 1 wt%, or less than about 0.5 wt%. In certain exemplary embodiments the curcumin formulation is essentially anhydrous. The inclusion of little or no water in the additive is advantageous because the chemical stability of curcuminoids is greatest under dry conditions.

In certain exemplary embodiments, one or more additional components are included in the additive. Suitable additional components include, for example, lubricants, fillers, disintegrants, preservatives or stabilizers such as antioxidants, light stabilizers, radical scavengers and stabilizers against microbial attack, dyes such as azo dyes, organic or inorganic pigments such as iron oxides or titanium dioxide, or dyes of natural origin, pH regulators, as well as compounds which alter or mask flavour and/or odour of the additive such as sweeteners, flavorings and odorants.

In certain exemplary embodiments, the additive is in the form of a solid dispersion product. In other words, at least part of the curcuminoid(s) is/are homogeneously distributed in a matrix of the phosphatide(s) and the dextrin(s). It is particularly preferred that the curcuminoid(s) in the solid dispersion product is/are present in an essentially non-crystalline state. This encompasses a state wherein essentially amorphous domains of curcuminoid(s) are interspersed in the matrix and a state wherein the curcuminoid(s) are molecularly dispersed in the matrix. When said

dispersion of the components is such that the system is chemically and physically uniform or homogeneous throughout or consists of one phase (as defined in

thermodynamics), such a solid dispersion will be called a "solid solution" or a

"molecular dispersion". The state of molecular dispersion corresponds to the maximum possible homogenisation of the curcuminoid in the matrix.

Known analytical methods can be used to investigate the state of such solid

dispersions, for example differential scanning calorimetry (DSC) or wide angle X-ray scattering measurements (WAXS measurements). The DSC analytical measurement of a substance in an essentially non-crystalline state lacks the melting peak which occurs with the crystalline pure substance and is usually endothermic. Another possibility for identifying an essentially non-crystalline state is the reduction in intensity and/or absence of typical X-ray diffraction signals in the WAXS analysis.

Providing the additive in the form of a solid dispersion product has the advantage that this maximises the water solubility of the one or more curcuminoid(s). This is at least in part because each particle of the solid dispersion product comprises a homogeneous distribution of the curcuminoid(s) in the maltodextrin and phosphatide(s) as opposed to each component being provided as separate particles. In particular, it is thought that the components form a complex which remains intact when the additive is dissolved in water. In addition, non-crystalline substances are in general easier to dissolve than crystalline substances. Solid dispersion products are known from WO 2012/049253, which is incorporated herein by reference.

Alternatively, the additive may be in the form of a dry blend. In the context of the present invention, a dry blend is a simple mixture of the curcuminoid(s), the

phosphatide(s) and the dextrin(s). As will be appreciated, when the additive is in the form of a dry blend, the curcuminoid(s), the phosphatide(s), the dextrin(s) and any other components of the additive are present as individual particles. In other words, the phosphatide and the dextrin(s) do not form a matrix in which at least part of the curcuminoid(s) is/are homogeneously dispersed. The synergistic effect of the dextrin(s) and the phosphatide(s) on the curcuminoid solubility has been found to occur even when the additive is in the form of a dry blend. Indeed, as will be shown by the

Examples, dry blends of the present invention provide curcuminoid solubility that is greater than or at least comparable to solid dispersion products in which isomaltulose is used instead of a dextrin having a dextrose equivalent of from 6 to 33. The fact that the synergistic effect occurs even for dry blends is advantageous because they are easier to manufacture than solid dispersion products. It is thought that upon dissolution of the additive in water, the curcuminoid(s), the phosphatide(s) and the dextrin(s) form a complex, thereby increasing the solubility of the curcuminoid(s).

In certain exemplary embodiments, the additive is in the form of a powder or granules. Powders are solid forms of the additive having an average particle diameter of less than 400 microns, as measured by static or dynamic light scattering. Granules are solid forms of the additive having an average particle diameter of from 0.5 to 3 mm. Both solid dispersion products and dry blends can be in the form of powders or granules. For example, a solid dispersion product in the form of a powder or granules can be obtained or is obtainable by milling or grinding a solid dispersion product in the form of a solidified extrudate. Thus, in other exemplary embodiments, the solid dispersion product is in the form of a solidified extrudate. A dry blend in the form of a powder or granules can be prepared by simply dry blending particulate curcuminoid(s), phosphatide and dextrin(s) to form a powder or granules, depending on the particle size. Granules can also be prepared by agglomerating the particles of a powder.

In certain preferred embodiments, the additive is obtained by or is obtainable by the method described herein.

The additives and nutritional compositions of the present invention provide improved oral bioavailability of the curcuminoid(s) compared to existing curcuminoid formulations, owing to the improved curcuminoid aqueous solubility. The oral bioavailability can be determined in experiments involving oral administration of the additive or nutritional composition of the invention to a subject and measuring the level of the curcuminoid(s) in a biological sample obtained from the subject over time, wherein the biological sample may be derived from a body fluid, for example serum, plasma, whole blood, or cerebrospinal fluid, and/or a tissue, e.g. from brain, liver, kidney or heart. For analysis, the curcuminoid level in the examined body fluid or tissue may be plotted against time, and the area under the curve (AUC), for example the total area under the curve from t=0 (time of administration) to t =∞ (= AUC0--), or the area under the curve within a

defined period, e.g. from t = 0 to t = 6 h (AUC0-6h) may be calculated. In general, a higher AUC relative to the AUC obtained by administration of non-formulated crystalline curcuminoid(s) indicates an improved bioavailability. The relative bioavailability may be calculated from the resulting AUC data as percentage based on the corresponding AUC data obtained from intravenous administration of curcuminoid(s).

In an especially preferred embodiment, the additive of the present invention is in the form of a solid dispersion product and comprises, by dry weight of the additive:

(i) one or more curcuminoids in a total amount of from about 2 to about 20 wt%;

(ii) one or more phosphatides in a total amount of from about 2 to about 20 wt%; and

(iii) one or more dextrins having a dextrose equivalent of from 20 to 30 in a total amount of from about 60 to about 96 wt%.

In a further especially preferred embodiment, the additive of the present invention is in the form of a dry blend and comprises, by dry weight of the additive:

(i) one or more curcuminoids in a total amount of from about 2 to about 20 wt%;

(ii) one or more phosphatides in a total amount of from about 2 to about 20 wt%; and

(iii) one or more dextrins having a dextrose equivalent of from 20 to 30 in a total amount of from about 60 to about 96 wt%.

In a further especially preferred embodiment, the additive of the present invention is in the form of a solid dispersion product and comprises, by dry weight of the additive:

(i) tetrahydrocurcumin (THC) in a total amount of from about 2 to about 20 wt%;

(ii) lecithin in a total amount of from about 2 to about 20 wt%; and

(iii) one or more dextrins having a dextrose equivalent of from 20 to 30 in a total amount of from about 60 to about 96 wt%.

In a further especially preferred embodiment, the additive of the present invention is in the form of a dry blend and comprises, by dry weight of the additive:

(i) tetrahydrocurcumin (THC) in a total amount of from about 2 to about 20 wt%;

(ϋ) lecithin in a total amount of from about 2 to about 20 wt%; and

(iii) one or more dextrins having a dextrose equivalent of from 20 to 30 in a total amount of from about 60 to about 96 wt%.

In each of these especially preferred embodiments, the additive preferably consists essentially of or consists of the components (i), (ii) and (iii).

In a second aspect, the present invention is directed to a nutritional composition comprising an additive as described herein and at least one of a protein, a

carbohydrate and a fat. In other words, the present invention is directed to a nutritional composition fortified with an additive as described herein. Preferably, the nutritional composition comprises protein, carbohydrate and fat. The nutritional compositions described provide improved curcuminoid solubility and bioavailability relative to existing nutritional compositions. Advantageously, where the additive is provided in the form of a dry blend, the entire process for preparing the nutritional composition does not involve substantial modification of conventional processes in the field.

In certain exemplary embodiments, the nutritional composition is formulated in a product form suitable for oral administration. Oral administration, as defined herein, includes any form of administration in which the composition is introduced into the subject's digestive system, including the stomach and small intestine. For example, oral administration includes nasogastric intubation, in which a tube is run from through the nose to the stomach of the subject to administer food or drugs. Suitable forms of such compositions may include liquids, powders, solids, semi-solids, semi-liquids compositions, provided that such a formulation allows for the effective delivery and consumption of the nutritional composition.

In certain exemplary embodiments, the composition may be a solid, liquid, semi-solid, semi-liquid, or powder. Examples of composition forms suitable for use herein include snack and meal replacement products, including those formulated as bars; sticks; cookies; breads, cakes, or other baked goods; frozen liquids; candy; breakfast cereals; powders, granulated solids, or other particulates; snack chips or bites; frozen or

retorted entrees; tablets and so forth. In certain exemplary embodiments, the nutritional composition can be in a form that falls between solid and liquid, such as puddings, yogurts, or gels.

Examples of suitable liquid nutritional compositions include snack and meal replacement products, hot or cold beverages, carbonated or non-carbonated beverages, juices or other acidified beverages, milk or soy-based beverages, shakes, coffees, teas, and so forth. These liquid compositions are most typically formulated as suspensions or emulsions, but can also be formulated in any other suitable form such as clear liquids, substantially clear liquids, liquid gels, and so forth.

The amount of protein, carbohydrate and fat, where present in the nutritional composition, can vary considerably depending upon the particular product form (e.g., bars or other solid dosage forms, milk or soy-based liquids or other clear beverages, reconstitutable powders, etc.) and the various other formulations and targeted dietary needs.

In certain exemplary embodiments, the nutritional composition comprises from about 1 to about 80 wt% protein by dry weight of the composition, or from about 5 to about 60 wt%, or from about 10 to about 40 wt%, or from about 10 to about 30 wt%, or from about 10 to about 20 wt%. It is to be understood that these amounts of protein are in addition to any protein that may be present in the additive.

Various sources of protein, including one source or more than one source, may be utilized in nutritional compositions according to the exemplary embodiments. Proteins suitable for use in the nutritional compositions according to the embodiments disclosed herein include, but are not limited to, hydrolyzed, partially hydrolyzed or non-hydrolyzed proteins or protein sources, and can be derived from any known or otherwise suitable source such as milk (e.g., casein, whey), animal {e.g., meat, fish), cereal {e.g., rice, corn), vegetable {e.g., soy, pea, potato), or combinations thereof.

Non-limiting examples of the source of protein include whey protein concentrates, whey protein isolates, whey protein hydrolysates, acid caseins, sodium caseinates, calcium caseinates, potassium caseinates, casein hydrolysates, milk protein concentrates, milk protein isolates, milk protein hydrolysates, skim milk, low fat milk, nonfat dry milk, skim milk powder, condensed skim milk, soy protein concentrates, soy protein isolates, soy protein hydrolysates, pea protein concentrates, pea protein isolates, pea protein hydrolysates, collagen proteins, collagen protein isolates, insect proteins, earthworm proteins, potato protein, rice protein, corn protein, wheat protein, sunflower protein, chickpea protein, quinoa protein, and combinations thereof.

In certain exemplary embodiments, the nutritional composition comprises from about 1 to about 80 wt% fat by dry weight of the composition, or from about 5 to about 60 wt%, or from about 10 to about 40 wt%, or from about 10 to about 30 wt%, or from about 10 to about 20 wt%. It is to be understood that these amounts of fat are in addition to any fat that is present in the additive, for example the phosphatide.

Non-limiting examples of fats suitable for use in the exemplary nutritional compositions include canola oil, corn oil, coconut oil, fractionated coconut oil, soy oil, olive oil, safflower oil, high GLA safflower oil, high oleic safflower oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, palm and palm kernel oils, palm olein, marine oils, cottonseed oils, algal and fungal derived oils, and combinations thereof.

In certain exemplary embodiments, the nutritional composition comprises from about 1 to about 80 wt% carbohydrate by dry weight of the composition, or from about 5 to about 60 wt%, or from about 10 to about 40 wt%, or from about 10 to about 30 wt%, or from about 10 to about 20 wt%. It is to be understood that these amounts of carbohydrate are in addition to any carbohydrate that is present in the additive, for example the dextrin.

The carbohydrates may be simple, complex, or variations or combinations thereof. Generally, any source of carbohydrates may be used so long as it is suitable for use in oral nutritional compositions and is otherwise compatible with any other selected ingredient or feature present in the nutritional composition. Non-limiting examples of a source of carbohydrates which may be suitable for use in the exemplary nutritional compositions described herein include maltodextrin, hydrolyzed or modified starch or cornstarch, glucose polymers, corn syrup, corn syrup solids, rice-derived

carbohydrates, sucrose, glucose, fructose, lactose, high fructose corn syrup, honey, sugar alcohols {e.g., maltitol, erythritol, sorbitol), isomaltulose, sucromalt, pullulan, potato starch, and other slowly-digested carbohydrates, dietary fibers including, but not limited to, oat fiber, soy fiber, gum arabic, sodium carboxymethylcellulose,

methylcellulose, guar gum, gellan gum, locust bean gum, konjac flour, hydroxypropyl methylcellulose, tragacanth gum, karaya gum, gum acacia, chitosan, arabinoglactins, glucomannan, xanthan gum, alginate, pectin, low and high methoxy pectin, cereal beta-glucans {e.g., oat beta-glucan, barley beta-glucan), carrageenan and psyllium,

Fibersol™, other resistant starches, and combinations thereof. It is to be understood that where the carbohydrates include maltodextrin or any other dextrin having a dextrose equivalent of from 6 to 33, this is in addition to the dextrin(s) present as part of the additive.

In certain exemplary embodiments, the nutritional composition comprises from about 1 to about 60 wt% of the additive by dry weight of the composition, or from about 5 to about 50 wt%, or from about 10 to about 40 wt%, or from about 20 to about 30 wt%.

In certain exemplary embodiments, the nutritional composition comprises at least one vitamin and/or at least one mineral. For example, in certain exemplary embodiments, the nutritional combination comprises vitamins and minerals that have antioxidant properties such as vitamin E, Vitamin C, selenium, molybdenum, and combinations thereof. In certain exemplary embodiments, the nutritional combination comprises vitamin D, including vitamin D2 and vitamin D3, which promotes intestinal absorption of calcium and phosphate.

In certain exemplary embodiments, the nutritional composition includes other vitamins and related nutrients, non-limiting examples of which include vitamin A, vitamin A palmitate, vitamin E acetate, vitamin C palmitate (ascorbyl palmitate), vitamin K, thiamine, riboflavin, pyridoxine, vitamin B12, carotenoids (e.g., beta-carotene, zeaxanthin, lutein, lycopene), niacin, folic acid, pantothenic acid, biotin, choline, inositol, salts and derivatives thereof, and combinations thereof. In certain exemplary embodiments, the nutritional composition comprises any of a variety of additional minerals, non-limiting examples of which include calcium, potassium, iodine,

phosphorus, magnesium, iron, zinc, manganese, copper, sodium, chromium, chloride, and combinations thereof.

In certain exemplary embodiments, the nutritional composition comprises a flowing agent or anti-caking agent to retard clumping or caking of a powder embodiment over time and to make the powder flow easily from its container. Any flowing or anti-caking agents that are known or otherwise suitable for use in a powder are suitable for use herein, non-limiting examples of which include tricalcium phosphate, silicates, and combinations thereof. The concentration of the flowing agent or anti-caking agent will often vary depending upon the product form, the other selected ingredients, the desired flow properties, and so forth.

In certain exemplary embodiments, the nutritional composition comprises a stabilizer. Any stabilizer that is known or otherwise suitable for use in a nutritional combination may also be suitable for use herein, non-limiting examples of which include gums such as xanthan gum and locust bean gum.

In certain exemplary embodiments, the nutritional composition includes one or more masking agents to reduce or otherwise obscure the development of any residual bitter flavors and after taste in the combination over time. Suitable masking agents include natural and artificial sweeteners, sodium sources such as sodium chloride, and hydrocolloids such as guar gum, xanthan gum, carrageenan, gellan gum, and combinations thereof. The amount of masking agent used will often vary depending upon the particular masking agent selected, other ingredients in the formulation, and other formulation or product target variables.

Exemplary embodiments of the nutritional composition may also be substantially free of any optional or selected essential ingredient or feature described herein, provided that the remaining product still contains some of the required ingredients or features as described herein. In this context, the term "substantially free" means that the nutritional composition contains less than a functional amount of the noted optional or selected essential ingredient, typically less than 1 %, including less than 0.5%, less than 0.1 %, and zero percent, by dry weight of the composition.

In certain exemplary embodiments, the nutritional composition is a nutritional liquid having a pH of from 6 to 8.

In certain preferred embodiments, the nutritional composition is obtained by or obtainable by the methods described herein. By providing the one or more

curcuminoids, the one or more phosphatides and the one or more dextrins as an additive during the manufacturing process, these components are associated with each other in the final nutritional composition. Where the nutritional composition is in the form of a liquid the components form non-covalent complexes in solution. Where the nutritional composition is in the form of a solid the components form non-covalent complexes upon reconstitution. Thus, in certain exemplary embodiments, the nutritional composition is a liquid comprising a non-covalent complex of the one or more curcuminoids, the one or more phosphatides and the one or more dextrins.

In an especially preferred embodiment, the nutritional composition of the present invention comprises, by dry weight of the composition:

from about 10 to about 40 wt% protein;

from about 10 to about 40 wt% fat;

from about 10 to about 40 wt% carbohydrate; and

from about 10 to about 40 wt% of the additive described herein.

In a third aspect, the present invention is directed to a nutritional composition as described herein for use in a method of treatment of a subject by therapy. The present invention also encompasses a method of treatment of a subject by therapy, the method comprising administering to the subject a nutritional composition as described herein.

In a fourth aspect, the present invention provides an aqueous non-covalent complex comprising:

(i) one or more curcuminoids;

(ii) one or more phosphatides; and

(iii) one or more dextrins having a dextrose equivalent of from 6 to 33.

As explained above, when an additive as described herein or a nutritional composition prepared therefrom is in liquid form or reconstituted, aqueous complexes of the one or more curcuminoids, the one or more phosphatides and the one or more dextrins are

formed. In the aqueous complex described herein, the one or more curcuminoids, the one or more phosphatides and the one or more dextrins are preferably present in the ratios described herein.

C. Methods of the invention

In a fifth aspect, the present invention is directed to a method of preparing an additive for a nutritional composition, the method comprising:

(a) blending one or more curcuminoids, one or more phosphatides, and one or more dextrins having a dextrose equivalent of from 6 to 33 to form a blend;

(b) heating the blend to form a homogeneous melt;

(c) forcing the homogeneous melt through one or more nozzles to form an extrudate; and

(d) solidifying the extrudate to form an additive in the form of a solid dispersion product.

The method of the present disclosure involves a number of steps. As will be appreciated, while these steps are intended to be sequential, there may be some overlap between the steps when the process is carried out in a continuous manner.

Step (a) involves blending one or more curcuminoids, one or more phosphatides, and one or more dextrins having a dextrose equivalent of from 6 to 33 to form a blend. In certain exemplary embodiments, the first step involves dry blending the components to form a dry blend. Preferably, the dry blend is the dry blend as described herein. Since the one or more dextrins act as a plasticizer in the context of the present invention, it is not necessary to add additional plasticizer. Other ingredients, such as vitamins and/or minerals, can be added to form part of the blend.

Step (b) involves heating the blend to form a homogeneous melt. The term "melt" should be interpreted broadly. In particular, the heating step may give rise to a transition from a solid state to a liquid state. Alternatively, however, the heating step may give rise to a transition to a glassy state or a rubbery state, so long as the curcuminoid(s) become embedded more or less homogeneously into the other components of the blend. In particular cases, one component will melt and the other

components will dissolve in the melt, thus forming a solution, which, upon cooling, may form a solid solution having advantageous dissolution properties. Thus, the melt may be in a liquid state, a rubbery state or a glassy state. Steps (a) and (b) may

conveniently be performed in a mixer or kneader which is jacketed for heating. In certain exemplary embodiments, the heating is carried out at a melt temperature of from 80 to 180 eC, or from 100 to 160 eC. Preferably step (b) is carried out in an extruder and the blend is subjected to a mixing action in a mixing section of the extruder.

Step (c) involves forcing the homogeneous melt through one or more nozzles to form an extrudate. Steps (a) to (c) may be performed in one or more than one apparatus suitable for this purpose, such as an extruder or kneader extruder.

Extruders are known per se. A suitable extruder for use in the method described herein is the Prism Eurolab Twin Extruder 16 from Thermo Scientific. An extruder comprises a housing or barrel divided into several sections in a longitudinal direction. On the upstream side of the extruder, an opening is provided for feeding powders of the curcuminoid(s), the phosphatide(s), the dextrin(s) and any further components such as the additional components described above. Usually, a hopper is placed on this opening so that the powder can be easily fed into the barrel of the extruder. The barrel ends in conveying direction in a die, where the dispersion is expelled.

The extruder may comprise at least one rotating shaft. Alternatively, it may comprise two or up to six rotating shafts. In preferred embodiments, the extruder is a twin-screw extruder. The shafts may be co-rotating or counter-rotating, but are preferably co-rotating. Processing elements disposed on adjacent shafts closely intermesh.

Each shaft carries a plurality of processing elements disposed axially one behind the other. The processing elements define a feeding and conveying section, at least one mixing section, and a discharging section. The feeding and conveying section is positioned farthest upstream, close to the hopper of the extruder, the at least one mixing section is positioned downstream of the feeding and conveying section, and the discharging section is positioned farthest downstream, close to the discharge opening of the extruder. The term "downstream" as used herein, refers to direction in which the material is being conveyed in the extruder, i.e. the conveying direction.

The processing elements of the feeding and conveying section as well as the discharging section are formed by screw-type elements. Preferably, these screw type elements form an endless screw having the feed direction and a uniform pitch flight. Thus, in the feeding and conveying section the powder is fed into the extruder and conveyed in the downstream direction, for example at a feed rate of 0.5 to 1 .5 kg/h, preferably of 0.5 to 1 .0 kg/h.

In the mixing section(s) the components to be processed are blended to form a blend (step (a)). Suitably, paddle means or kneading blocks may be used. These kneading blocks consist of cam disks mutually offset at an angle in a peripheral direction. The cam disks have abutting faces that are perpendicular to the general conveying direction in the extruder. Alternatively, the mixing section(s) are defined by processing elements) that comprise(s) a mixing element that is derived from a screw type element. A mixing element "being derived from a screw type element" is intended to mean an element whose basic shape is that of a screw element, but which has been modified such that it exerts a compounding or mixing effect in addition to a conveying effect. In a preferred embodiment of the invention, the extruder comprises one or more than one, for example three or four, mixing sections, which are connected by intermediate conveying sections formed by screw-type elements. The extruder shaft may further comprise one or more than one reverse-flight section(s), preferably arranged after the (last) mixing section and defined by reverse-flight elements. A reverse-flight element has a screw with a reverse-flight relative to the screw- type elements which may be arranged in the feeding and conveying section which define the general conveying direction of the extruder. Thus, the reverse-flight element convey the material in an opposite direction relative to the general conveying direction of the extruder and serves to create sufficient back-pressure to allow for a desired degree of mixing and/or homogenization. The reverse-flight element is designed to stow the material conveyed in the extruder.

Therefore it may also be called a back-pressure element.

The blend which is fed to the extruder is heated in order to form a homogeneous melt (step (b)). The curcuminoid(s) are dispersed, or preferably, dissolved in the matrix efficiently.

In certain exemplary embodiments, the barrel of the extruder is divided into several

heating zones. The temperature in these heating zones can be controlled in order to control the melting of the dispersion. Preferably, the portion of the barrel upstream of the first mixing element or first reverse-flight element is maintained at a lower temperature, e.g. a temperature of from about 50 to about 100°C, than the portion of the barrel downstream of the first mixing element that is kept at, for example, a temperature of from about 100 to about 150°C.

The consistency of the extrudate exiting from the extruder typically ranges from pasty to viscous. After step (c) and before step (d), the extrudate may be directly shaped into virtually any desired shape. Shaping of the extrudate may be conveniently carried out by a calender with two counter-rotating rollers with mutually matching depressions on their surface. A broad range of tablet forms can be attained by using rollers with different forms of depressions. If the rollers do not have depressions on their surface, films can be obtained. Alternatively, the extrudate may be moulded into the desired shape by injection-moulding. Alternatively, the extrudate may be subjected to profile extrusion and cut into pieces, either before (hot-cut) or after solidification (cold-cut).

Step (d) involves cooling the extrudate to form an additive in the form of a solid dispersion product, in other words solidifying the extrudate. This cooling step may be active or passive. The cooling step is preferably passive. In other words, the extrudate is preferably allowed to solidify to form the solid dispersion product, without using active cooling means. Preferably, the solid dispersion product produced by the method is the solid dispersion product described herein.

In certain exemplary embodiments, the method further comprises grinding or milling the solid dispersion product to form an additive in the form of a powder or granules.

Alternatively, the method may further comprise grinding or milling the solid dispersion product to form a powder and then agglomerating the powder to form granules. The particle sizes for powders and granules are as described above.

In certain exemplary embodiments, the method further comprises compressing the powder or granules to form a tablet. This step is typically carried out in a tablet press.

In a sixth aspect, the present invention is directed to a method of preparing an additive for a nutritional composition, the method comprising dry blending one or more curcuminoids, one or more phosphatides, and one or more dextrins having a dextrose equivalent of from 6 to 33 to form an additive in the form of a dry blend. Dry blending may, for example, be carried out in a mini turbula blender, for example at 60 rpm for 1 hour. Suitable dry blending conditions will vary depending on the composition of the dry blend and can be determined by those skilled in the art.

In a seventh aspect, the present invention is directed to a method of preparing an additive for a nutritional composition, the method comprising wet blending one or more curcuminoids, one or more phosphatides, and one or more dextrins having a dextrose equivalent of from 6 to 33 to form a wet blend, and

drying the wet blend to form an additive.

By "wet blending" it is meant that the components are combined in aqueous solution or slurry form, to form an aqueous solution or slurry of the components.

In certain exemplary embodiments, the step of drying the wet blend to form an additive is a step of spray drying. Alternatively, the step of drying the wet blend to form an additive may be a step of freeze drying. Alternatively, the step of drying the wet blend to form an additive may be a step of solvent evaporation. These techniques are well known to those skilled in the art.

In an eighth aspect, the present invention is directed to a method of preparing a nutritional composition, the method comprising:

(a) forming an additive according to a method as described herein, or providing an additive as described herein; and

(b) mixing the additive with at least one of a protein, a carbohydrate and a fat to form a nutritional composition.

Preferably, the nutritional composition is a nutritional composition as described herein.

In certain exemplary embodiments, step (a) is a step of providing or forming the additive in the form of a powder or granules, and step (b) is a step of dry blending the additive with at least one of a protein, a carbohydrate and a fat to form a nutritional powder.

Alternatively, step (b) may be a step of mixing the additive with a slurry comprising at least one of a protein, a carbohydrate and a fat to form a supplemented slurry. The supplemented slurry may then be dried to form a nutritional powder, for example by spray-drying. Many different spray-drying methods and techniques are known for use in the nutrition field, of which many are suitable for use in the manufacture of the spray-dried nutritional powders herein.

Alternatively, where step (b) is a step of mixing the additive with a slurry comprising at least one of a protein, a carbohydrate and a fat to form a supplemented slurry, the supplemented slurry may be subjected to one or more additional treatment steps to form a nutritional liquid. In certain exemplary embodiments, the supplemented slurry is pH-adjusted to a desired range, typically from 6.6 to 7.0, after which the composition is subjected to high-temperature short-time (HTST) processing during which the composition is heat treated, emulsified and homogenized, and then allowed to cool. Water-soluble vitamins and ascorbic acid are added, the pH is again adjusted to the desired range (if necessary), flavours are added, and water is added to achieve a desired total solid level. The composition is then aseptically packaged to form an aseptically packaged nutritional emulsion, or the composition is added to retort stable containers and then subjected to retort sterilization to form a retort sterilized nutritional emulsion.

As will be appreciated, the mixing of the additive with the other components of the nutritional composition can take place at any stage of the manufacturing process. For example, the additive may be added after the HTST processing. Moreover, where several, separate slurries are prepared and then blended together, such as a protein-in-fat (PIF) slurry, a carbohydrate-mineral (CHO-MIN) slurry, and a protein-in-water (PIW) slurry, the additive may be mixed with one or more of these slurries before they are blended together (and subsequently pH-adjusted, heat-treated etc.). Alternatively, the additive may be mixed with the blend of the slurries.

As will be appreciated, where the additive is provided or formed as a dry blend, the process has the advantage that a nutritional composition can be preparing having a high curcuminoid solubility and/or bioavailability without requiring any real modification of conventional manufacturing processes for nutritional compositions.

In certain exemplary embodiments, where the nutritional composition is in the form of a powder, the method further comprises compressing the powder to form a tablet.

In a ninth aspect, the present invention is directed to the use of a combination of one or more phosphatides and one or more dextrins having a dextrose equivalent of from 6 to 33 as an aqueous solubility enhancer for a curcuminoid.

Aqueous solubility enhancement may be measured as an increase in saturation solubility (μς/ηιί) of the curcuminoid in water at pH 7 and at 25 eC by at least 50% relative to the same amount of curcuminoid on its own, or by at least 70%, or by at least 90%, or by at least 100%, or by at least 150%, or by at least 200%. For example, aqueous solubility enhancement may be measured as an increase in solubility (μς/ηιί) of 0.25 wt% or 0.75 wt% curcuminoid in water at pH 7 and at 25 eC by the

aforementioned amounts. The curcuminoid solubility of a composition can be measured by adding the composition in powdered form to 10 mL water to give, for example, 0.25 wt% or 0.75 wt% curcuminoid in water, forming a suspension by vigorous vortexing, placing the suspension on an orbital shaker for 12 hours, centrifuging 1 .5 mL of the suspension at 13,000 g for 6 min to form a solid residue and a supernatant, filtering the supernatant to form a filtered solution, and determining the concentration of the curcuminoid in the filtered solution (for example by HPLC analysis). Whether 0.25 wt% or 0.75 wt% is chosen as the amount of curcuminoid to disperse in water, it is above the solubility limit for curcuminoids as measured under these conditions. This ensures that the aqueous solutions are saturated with curcuminoid, enabling the method to give a true measure of curcuminoid solubility (the saturation solubility).

In certain exemplary embodiments, the one or more dextrins are used in a weight ratio of from about 1 :2 to about 1 :20 relative to the total weight of the curcuminoids, or from about 1 :4 to 1 :12, or about 1 :6 to 1 :10, or about 1 :8. As will be appreciated, these weight ratios refer to the total amount of the one or more dextrins and the total amount of the one or more phosphatides.

In certain exemplary embodiments, the one or more phosphatides are used in a weight ratio of from about 1 :3 to about 3:1 relative to the total weight of the curcuminoids, or from about 1 :2 to 2:1 , or about 1 :1 . As will be appreciated, these weight ratios refer to the total amount of the one or more curcuminoids and the total amount of the one or more phosphatides.

In certain exemplary embodiments, the one or more phosphatides are used in a weight ratio of from about 1 :2 to about 1 :20 relative to the total weight of the one or more dextrins, or from about 1 :4 to 1 :12, or about 1 :6 to 1 :10, or about 1 :8. As will be appreciated, these weight ratios refer to the total amount of the one or more phosphatides and the total amount of the one or more dextrins.

In certain preferred embodiments, the one or more phosphatides is lecithin, and the curcuminoid is THC and the one or more dextrins have a dextrose equivalent of from 20 to 29.

The present invention will now be described in relation to the following non-limiting examples.

EXAMPLES

Example 1

Various dry blends and solid dispersions containing tetrahydrocurcumin (THC) were prepared in accordance with the samples listed in the table below and the water solubility of the THC in each sample was determined by the following method.

For each sample, an amount of sample containing 25 mg THC was weighed in a 15 mL centrifuge tube and 10 mL of water was added, thus preparing an aqueous solution having a total of 0.25 wt% THC dissolved or dispersed therein. The sample was vortexed vigorously for 30 seconds to obtain a suspension and then placed on an

orbital shaker for 12 hours. A 1 .5 mL portion of suspension was transferred to a micro centrifuge tube and centrifuged at 13,000 g for 6 min. The supernatant was filtered through 0.45 μηι cellulose membrane. A 0.4 mL portion of filtrate was transferred into a 10 mL volumetric flask, topped with DMSO to volume, and inverted to mix well. The sample was then transferred into a 2 mL HPLC vial for the concentration of THC in solution to be determined.

The THC concentration in each HPLC sample was determined by comparing the THC peak with the standards described below, and the concentration that would have been present in the filtrate prior to dilution with DMSO was calculated.

Measurement of sample THC content

Sample (-25 mg) was weighed in a 25 mL volumetric flask, and 1 mL of water was added to disperse the particles. After vortexing for 30 second, the sample was topped with DMSO to the volume, and inverted to mix well. It was then filtered through 0.2 μηι FTPE membrane into a 2 mL HPLC vial for the THC concentration in the solution to be measured and the sample THC content to be calculated therefrom.

This measurement was carried out because the THC content of the sample might be expected to deviate slightly from the concentration expected from the quantities of raw materials used, for example as a result of some THC decomposing during the melt extrusion step.

Standard preparation

Stock standard solution was prepared by accurately weighting 75 mg of C3 Reduct® ODN (a commercial source of THC) into 100 mL volumetric flask and topped up to mark with 96% DMSO in water. Further dilutions with 96% DMSO in water were carried out to make 15, 30, 75 and 150 μg/mL working standard solutions.

HPLC method

Instrument Parameters:


Results:

Sample Description Processing THC THC aqueous content solubility

(mg/g) (Mg/mL) at 0.25 wt%

THC white curcumin None NA 66.2

(comparative) (wc)

PM-3 50% wc + 50% Physical mixing NA 99

(comparative) lecithin

PM-1 10% wc + 90% Physical mixing 97.2 69.6

(comparative) corn syrup solids

PM 10% wc + 10% Physical mixing 90.5 126

lecithin + 80%

corn syrup solids

Formulation A 10% wc + 10% Extrusion @ 74.1 151

lecithin + 80% 1 10eC, 125 rpm

corn syrup solids screw speed then

grinding

Formulation B 10% wc + 10% Extrusion @ 84.1 156

lecithin + 80% 130eC, 125 rpm

corn syrup solids screw speed then

grinding

Formulation C 10% wc + 10% Extrusion @ 82.2 152

lecithin + 80% 120eC, 125 rpm

corn syrup solids screw speed then

grinding

Formulation D 10% wc + 10% Extrusion @ 90.4 154

lecithin + 80% 120eC, 200 rpm

corn syrup solids screw speed then

grinding

PM-2 10% wc + 10% Physical mixing 138.3 107

(comparative) lecithin + 80%

isomaltulose

Formulation E 10% wc + 10% Extrusion @ 82.6 1 18

(comparative) lecithin + 80% 1 10eC, 125 rpm

isomaltulose screw speed then

grinding

Formulation F 10% wc + 10% Extrusion @ 90.5 121

(comparative) lecithin + 80% 1 10eC, 200 rpm

isomaltulose screw speed then

grinding

Formulation G 10% wc + 10% Extrusion @ 91 .7 131

(comparative) lecithin + 80% 120eC, 125 rpm

isomaltulose screw speed then

grinding

Formulation H 10% wc + 10% Extrusion @ 95.7 123

(comparative) lecithin + 80% 120eC, 200 rpm

isomaltulose screw speed then

grinding

The "corn syrup solids" used in the Examples are dextrins having a dextrose equivalent of 25. The lecithin used was soy lecithin having an HLB of 7. A Prism Eurolab Twin Extruder 16 from Thermo Scientific was used in the preparation of the extruded samples.

The THC aqueous solubility for each formulation relative to the THC ingredient alone is shown in the following table:


As can be seen from the data for the physical mixtures, lecithin alone increases the solubility of THC while corn syrup solids alone have a negligible effect. The effect of lecithin and corn syrup solids in combination is significantly greater than the sum of the individual effects. Thus, lecithin and corn syrup solids interact synergistically to improve the solubility of THC. All of the solid dispersion samples comprising corn syrup solids and lecithin exhibited greater THC solubility than the corresponding physical mixture. The parameters used for the melt extrusion had little effect on the THC solubility in the resulting solid dispersion.

By contrast, lecithin and isomaltulose provide only slightly higher THC solubility (162%) than lecithin alone (150%). Thus, there is no synergistic interaction between lecithin and isomaltulose with respect to THC solubilisation.

The data also show that a dry blend of THC, lecithin and corn syrup solids has a THC solubility (190%) that is higher than or at least comparable to solid dispersions of THC in lecithin and isomaltulose (178%, 183%, 198% and 186%), despite the fact that in the solid dispersions the THC is homogeneously dispersed in a matrix of the lecithin and isomaltulose.

Example 2

For each sample, an amount of sample containing 75 mg THC was weighed in a 15 ml_ centrifuge tube and 10 mL of water was added, thus preparing an aqueous solution having a total of 0.75 wt% THC dissolved or dispersed therein. The THC content and THC aqueous solubility of each sample was measured in accordance with the method of Example 1 . The results were as follows:

Sample THC content (mg/g) THC aqueous solubility ( g/mL) at 0.75 wt%

THC NA 1 13

(comparative)

PM-3 NA 239

(comparative)

Formulation E 82.5 251

(comparative)

Formulation B 79.2 436

Example 3

The following samples were prepared to compare the THC solubility of samples containing lipophilic soy lecithin (HLB 7) with that of samples containing hydrophilic soy lecithin (HLB 9). The THC content of each sample was measured in accordance with the method of Example 1 .

Sample Description Processing THC

content

(mg/g)

White curcumin white curcumin (wc) None NA

5% THC - HLB 5% wc + 10% lecithin Extrusion @ 120eC, 200 47.2 7 (Extruded) (HLB 7) + 85% corn syrup rpm screw speed then

solids grinding

5% THC - HLB 5% wc + 10% lecithin Physical mixing 50.9 7 (Dry blend) (HLB 7) + 85% corn syrup

solids

5% THC - HLB 5% wc + 10% lecithin Extrusion @ 120eC, 200 49.3 9 (Extruded) (HLB 9) + 85% corn syrup rpm screw speed then

solids grinding

5% THC - HLB 5% wc + 10% lecithin Physical mixing 34.3 9 (Dry blend) (HLB 9) + 85% corn syrup

solids

7.5% THC - 7.5% wc + 10% lecithin Extrusion @ 120eC, 200 79.2 HLB 7 (HLB 7) + 82.5% corn rpm screw speed then

(Extruded) syrup solids grinding

7.5% THC - 7.5% wc + 10% lecithin Physical mixing 62.4

HLB 7 (Dry (HLB 7) + 82.5% corn

blend) syrup solids

7.5% THC - 7.5% wc + 10% lecithin Extrusion @ 120eC, 200 72

HLB 9 (HLB 9) + 82.5% corn rpm screw speed then

(extruded) syrup solids grinding

7.5% THC - 7.5% wc + 10% lecithin Physical mixing 64

HLB 9 (dry (HLB 9) + 82.5% corn

blend) syrup solids

The "corn syrup solids" are dextrins having a dextrose equivalent of 25.

The THC aqueous solubility of each sample was measured at 0.75 wt% THC in accordance with the method of Example 1 . The results are shown in Figure 1 .

The data show that samples containing hydrophilic lecithin (HLB 9) were more effective at solubilising THC than samples containing lipophilic lecithin (HLB 7). All samples exhibited significantly greater THC solubility than the THC control.

The error bars indicate standard error of the mean (SEM).