FIELD OF THE INVENTION
The present invention is directed to combinations comprising beta-hydroxy beta-methylbutyrate (HMB) and tetrahydrocurcumin (THC). Such combinations have been found to be particularly useful in attenuating muscle protein degradation, preserving lean body mass, or both in a subject in need thereof.
BACKGROUND
Loss of lean body mass occurs with aging, muscle disuse, surgery, and a number of catabolic conditions including, but not limited to, cancer, burn injuries, chronic obstructive pulmonary disease, congestive heart failure, and chronic kidney disease. Such loss of lean body mass leads to functional decline, loss of independence, and increased disease burden. The loss of lean body mass is commonly attributed to an imbalance with the rate of muscle protein degradation outpacing the rate of muscle protein synthesis.
One compound that has been demonstrated to be useful in attenuating muscle protein degradation and preserving lean body mass is beta-hydroxy beta-methylbutyrate (HMB), a metabolite of branched chain amino acid, leucine. HMB has been shown to increase protein synthesis and decrease protein degradation. Traditionally, HMB has been used by athletes to enhance performance and build lean body mass. Recent research has focused on the use of HMB to preserve or rebuild muscle mass in populations with sarcopenia, immobility due to prolonged bed rest and post-surgery. Data have also demonstrated the benefits of HMB supplementation in preserving lean body mass and muscle strength in the elderly as well as in persons with chronic diseases such as AIDS and cancer (see for example WO 2012/092035 and WO 2012/097061 ). These benefits occur at a certain minimum dose of HMB (50 mg/kg/day for humans) (Deutz NE, Pereira SL, Hays NP, Oliver JS, Edens NK, Evans CM, et al. Effect of beta-hydroxy-beta-methylbutyrate (HMB) on lean body mass during 10 days of bed rest in older adults. Clin Nutr. 2013;32:704-12). The beneficial effects of HMB have been postulated to be mediated by the Phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonin protein kinase (AKT)/mammalian target of rapamycin kinase (mTOR) signaling pathway.
Nevertheless, HMB is expensive and compositions comprising HMB are difficult to prepare. This is because HMB is difficult to handle, requiring many special provisions that reduce manufacturing efficiency. There is therefore a need to develop compositions having a similar effect in attenuating muscle protein degradation and preserving lean body mass to existing HMB compositions.
SUMMARY OF INVENTION
The present inventors have found that a combination comprising beta-hydroxy beta-methylbutyrate (HMB) and tetrahydrocurcumin (THC) can be used to attenuate muscle protein degradation, preserve lean body mass, or both in a subject in need thereof.
Surprisingly, it has been found that if THC is used with HMB, a lower dose of HMB can be used to achieve attenuation of muscle protein degradation as compared with HMB-containing combinations without THC. This allows HMB to be administered at a lower dose than is normally expected to be effective (for example, half the conventional dose of 50 mg/kg/day).
In a first aspect, the present invention provides a pharmaceutical or nutritional combination comprising beta-hydroxy beta-methylbutyrate (HMB) and tetrahydrocurcumin (THC).
In a second aspect, the present invention provides a method of manufacturing a
combination comprising beta-hydroxy beta-methylbutyrate (HMB) and tetrahydrocurcumin (THC), the method comprising mixing a source of HMB with a source of THC.
In a third aspect, the invention provides a method of treatment of a subject by therapy, the method comprising administering to the subject a pharmaceutical or nutritional combination comprising beta-hydroxy beta-methylbutyrate (HMB) and tetrahydrocurcumin (THC).
In a fourth aspect, the invention provides a method of attenuating muscle protein degradation and/or maintaining lean body mass in a subject in need thereof, the method comprising administering to the subject a pharmaceutical or nutritional combination comprising beta-hydroxy beta-methylbutyrate (HMB) and tetrahydrocurcumin (THC).

BRIEF DESCRIPTION OF DRAWINGS

Figure 1 shows the effects after 21 days of a composition comprising HMB and THC on soleus muscle mass (in grams) in rats that have been subjected to dexamethasone-induced muscle loss. Data for HMB alone and THC alone are also included as controls.

Figure 2 shows the effects after 21 days of the same compositions on rectus femoris muscle mass (in grams) in the rats.

Figure 3 shows the effects after 21 days of the same compositions on the lean mass of the rats (in grams).

Figure 4 shows the effects after 21 days of the same compositions on the fore limb grip strength (g force) of the rats.

Figure 5 shows the effects after 21 days of the same compositions on the hind limb grip strength (g force) of the rats.

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 term "pharmaceutical combination" as used herein refers to preparations which contain no additional components which are significantly toxic to the subjects to which the combination would be administered.

The phrase "pharmaceutically acceptable carrier" as used herein refers to a

pharmaceutically acceptable material, combination or vehicle, suitable for administration to mammals. The carriers include liquid or solid filler, diluent, excipient, solvent or

encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to or impacting safety of the patient.

"Pharmaceutically acceptable excipients" (vehicles, additives) are those which can reasonably be administered to a subject mammal to provide an effective dose of the active ingredient employed. The term "excipient" refers to an agent which may be added to a formulation to provide a desired consistency, e.g., altering the bulk properties, to improve stability, and/or to adjust osmolality. Examples of commonly used excipients include, but are not limited to, sugars, polyols, amino acids, surfactants, and polymers.

The terms "nutritional formula" or "nutritional product" or "nutritional combination," as used herein, are used interchangeably and, unless otherwise specified, refer 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, unless otherwise specified, 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, unless otherwise specified, 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, unless otherwise specified, refers to nutritional products that are intermediate in properties, such as rigidity, between solids and liquids. Some semi-solids examples include puddings, gelatins, and doughs.

The term "nutritional semi-liquid," as used herein, unless otherwise specified, 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, and unless otherwise specified, 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, and unless otherwise specified, 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, unless otherwise specified, should be understood to include providing a nutritional combination to a subject, the act of consuming a nutritional combination (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, unless otherwise specified, 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 "subject in need thereof," as used herein, unless otherwise specified, refers to a subject exhibiting increased muscle protein degradation, decreased muscle protein synthesis, loss of lean body mass, or combinations thereof. In certain exemplary embodiments, the increased muscle protein degradation, decreased muscle protein synthesis, or loss of lean body mass may be due to, at least in part, age, physical inactivity, injury, surgery, chronic disease, or combinations thereof. In certain exemplary

embodiments, the subject in need thereof is an elderly human, optionally a physically inactive elderly human, optionally a diseased elderly human, and optionally both physically inactive and diseased. In certain exemplary embodiments, the subject in need thereof, is a human that is undergoing a temporary or permanent period of physical inactivity, due to disability, temporary injury, or healing from a surgery. In certain exemplary embodiments, the subject in need thereof has undergone hip surgery. In certain exemplary embodiments,

the subject in need thereof has suffered a burn injury, for example, a third degree burn injury. In certain exemplary embodiments, the subject in need thereof is a human undergoing rehabilitation (i.e. , physical rehabilitation) due to disease, injury, surgery, hospital admission, and combinations thereof. In certain exemplary embodiments, the subject in need thereof is a human with a chronic disease condition such as, for example, cancer, cachexia, COPD, or end stage renal disease. In certain exemplary embodiments, the subject in need thereof is a human being treated with glucocorticoids for an extended period of time. In certain exemplary embodiments, the subject in need thereof is a human suffering from a muscle disease such as, for example, muscular dystrophy.

The term "elderly," as used herein, unless otherwise specified, refers to a human of at least 45 years of age, including at least 50 years of age, at least 55 years of age, at least 60 years of age, at least 65 years of age, at least 70 years of age, at least 75 years of age, and including at least 80 years of age or greater. The term "elderly" also includes humans of 45 years of age to 100 years of age, and humans of 55 years of age to 80 years of age.

The term "lean body mass," as used herein, unless otherwise specified, refers to the amount or size of muscle or muscle groups, as expressed by muscle weight, mass, area, or volume. Muscle mass may also be expressed as total muscle mass, lean body mass of a body compartment such as the leg, or cross-sectional area of a leg or arm compartment. The volume or mass of the muscle can be determined using any known or otherwise effective technique that provides muscle area, volume, or mass such as DEXA, or using visual or imaging techniques such as MRI or CT scans.

The term "muscle," as used herein, unless otherwise specified, refers to skeletal muscle and other non-skeletal, striated muscles such as diaphragm, extraocular muscle, and so forth.

The term "effective amount," as used herein, unless otherwise specified, refers to a sufficient amount of a combination to exhibit a therapeutic effect (e.g. , attenuate muscle protein degradation, preserve lean body mass). The exact amount required to achieve the desired effect will vary from subject to subject, depending on the species, age, weight, lifestyle and general condition of the particular subject.

The term "serving" as used herein, unless otherwise specified, refers to an amount of the combination which is intended to be consumed by an individual in one sitting or within one hour or less. In certain exemplary embodiments, the combination is packaged as a single serving. In certain exemplary embodiments, the combination is packaged in a container containing multiple servings, wherein the container bears instructions on how to separate a single serving of the combination from the bulk combination. Unless otherwise specified, when referring to a liquid combination, the term serving refers to a 230 mL portion. Unless otherwise specified, when referring to a solid combination, the term serving refers to a 54 g serving.

The term "THC", as used herein, unless otherwise specified, refers to tetrahydrocurcumin, and other suitable sources of THC 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 HMB suitable for oral administration. THC is also known as white curcumin and 1 ,7-bis(4-hydroxy-3-methoxyphenyl)heptane-3,5-dione.

The term "HMB," as used herein, unless otherwise specified, refers to β-Ι^Γθχν-β-methylbutyrate (or beta-hydroxy-beta-methylbutyrate), and other suitable sources of HMB 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 HMB suitable for oral administration.

All percentages, parts and ratios as used herein, are by dry weight of the total combination, 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 combination is a solid, the percentages are based on the total weight of the combination prior to reconstitution. Where the combination is a liquid, the percentages are based on the total weight of the combination minus the solvent, in other words by dry weight of the combination.

Numerical ranges as used herein are intended to include every number and subset of numbers within that range, whether specifically disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be

construed as supporting a range of from 2 to 8, from 3 to 7, from 5 to 6, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

All references to singular characteristics or limitations of the present disclosure shall include the corresponding plural characteristic or limitation, and vice versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made. Unless otherwise specified, "a," "an," "the," and "at least one" are used

interchangeably. Furthermore, as used in the description and the appended claims, the singular forms "a," "an," and "the" are inclusive of their plural forms, unless the context clearly indicates otherwise.

All combinations of method or process steps as used herein can be performed in any order, unless otherwise specified or clearly implied to the contrary by the context in which the referenced combination is made.

In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary.

B. Combinations of the invention and methods of manufacture

In a first aspect, the present invention is directed to a pharmaceutical or nutritional combination comprising, consisting essentially of or consisting of beta-hydroxy beta-methylbutyrate (HMB) and tetrahydrocurcumin (THC). In certain preferred embodiments, the combination is a nutritional combination.

At a certain minimum dose (typically 50 mg/kg/day for humans), HMB is known to be useful in preserving or rebuilding muscle mass and/or strength, for example in populations with sarcopenia, the elderly and persons with chronic diseases like AIDS and cancer.

Surprisingly, the present inventors have found that the inclusion of THC enables the minimum effective dose of HMB to be reduced. This is advantageous because HMB is expensive to incorporate into nutritional combinations, partly due to ingredient costs but also because it is difficult to handle, requiring many special provisions that reduce manufacturing efficiency. Accordingly, the present invention allows combinations to be

prepared having lower levels of HMB without compromising the effect on preserving or rebuilding muscle mass and/or strength.

HMB is a metabolite of the essential amino acid leucine, and has the lUPAC name 3-hydroxy-3-methylbutanoic acid. One suitable form of HMB that may be utilized in the exemplary nutritional combinations and methods described herein is the calcium salt of HMB, also designated as Ca-HMB, which is most typically the monohydrate calcium salt. The HMB used in the combinations of the exemplary embodiments may be obtained from any suitable source. Calcium HMB monohydrate (Ca-HMB) is commercially available from Technical Sourcing International (TSI) of Salt Lake City, Utah. The amounts of HMB to be incorporated into the combinations described herein are based on the calcium salt form of HMB. It would be within the capabilities of the skilled person to adjust the quantity depending on the source used to provide the desired amount of the free acid.

Although the monohydrate of the calcium salt may be utilized in certain exemplary embodiments of the nutritional combinations and methods disclosed herein, other suitable sources or forms include HMB as a free acid, a salt, an anhydrous salt, an ester, a lactone, or other product forms that provide a bioavailable form of HMB suitable for administration. Non-limiting examples of suitable salts of HMB include HMB salts, hydrated or anhydrous, of sodium, potassium, chromium, calcium, or other non-toxic salt forms.

In certain exemplary embodiments, the combination comprises from 0.5 to 2 wt% HMB by dry weight of the combination, preferably from 1 to 2 wt%, still more preferably from 1.3 to 1.7 wt%, and most preferably about 1.5 wt%. Thus, the exemplary combinations comprise significantly less HMB than conventional HMB-containing nutritional combinations used to preserve lean body mass or attenuate muscle protein degradation, which typically comprise about 3 wt% HMB by dry weight of the combination.

In certain exemplary embodiments, the combination comprises from 0.6 to 1.2 grams of HMB per serving, preferably from 0.7 to 0.9 grams per serving, and most preferably about 0.75 grams per serving. The serving size is as defined above. Thus, the exemplary combinations comprise significantly less HMB than conventional HMB-containing nutritional combinations, which typically comprise about 1.5 grams per serving HMB where a serving is defined on the above basis.

THC has been shown to exhibit protective physiological and pharmacological properties similar to curcumin (also known as yellow curcumin, found in ginger), such as anti-oxidant, radical scavenging, anti-metastatic, and anti-carcinogenic activities. However, while HMB has been widely reported to prevent muscle loss, there are no reports on the efficacy of THC against muscle loss. As is demonstrated in the Examples, the present inventors have surprisingly found that a combination of HMB and THC has a greater effect than the sum of the components individually. Thus, there is a synergy between the two components that allows the amount of HMB included in the formulation to be reduced.

The amounts of THC to be incorporated into the combinations described herein are based on the free acid. It would be within the capabilities of the skilled person to adjust the quantity depending if a salt form was used to provide the desired amount of the free acid.

In certain exemplary embodiments, the combination comprises from 0.5 to 1.5 wt% THC by dry weight of the composition, more preferably from 0.6 to 1.2 wt% and most preferably from 0.8 to 1 wt%.

In certain exemplary embodiments, the combination comprises from 0.05 to 3 grams of THC per serving, preferably from 0.2 to 1 grams per serving, more preferably from 0.2 to 0.8 grams per serving, and most preferably from 0.4 to 0.6 grams per serving. The serving size is as defined above.

In certain exemplary embodiments, the combination has a weight ratio of HMB to THC of from 1 :1 to 5:1 , preferably from 1 :1 to 3:1 , and most preferably from 1 :1 to 2:1.

In certain exemplary embodiments, the combination is a nutritional combination and comprises from 1 to 2 wt% HMB and from 0.5 to 1 .5 wt% THC by dry weight of the combination.

In certain exemplary embodiments, the combination is a nutritional combination and comprises from 0.6 to 1.2 grams per serving HMB and from 0.2 to 0.8 grams per serving THC, wherein a serving as defined as above.

In certain exemplary embodiments, the HMB and THC are provided in separate

compositions.

In certain preferred embodiments, the HMB and THC are provided in a single composition. Preferably, the combination consists of a single composition comprising HMB and THC. In other words, the combination is preferably a composition comprising HMB and THC.

Additional ingredients

In certain exemplary embodiments, the combination is a pharmaceutical combination. In other words, the combination contains no additional components which are significantly toxic to the subjects to which the combination would be administered. Preferably, where the combination is a pharmaceutical combination, the combination comprises one or more pharmaceutically acceptable excipients. As noted above, examples of commonly used excipients include, but are not limited to, sugars, polyols, amino acids, surfactants, and polymers.

In certain preferred embodiments, the combination is a nutritional combination. In other words, the combination comprises at least one of a protein, a carbohydrate or a fat.

In certain exemplary embodiments, the nutritional combination comprises a source of protein. In one exemplary embodiment, the source of protein is present in an amount sufficient to provide about 3 to about 30 grams, about 5 to about 15 grams, or about 7 to about 10 grams of protein per serving. Alternatively, the amount of protein present in the combination may be expressed in terms of percentage of protein by dry weight of the combination (wt%). In such instances, the combinations may comprise a source of protein in an amount sufficient to provide 5 to 50 wt% protein by dry weight of the combination, preferably from 10 to 30 wt%, more preferably from 10 to 20 wt%, and most preferably from 12 to 18 wt%.

Various proteins, including one protein or more than one protein, may be utilized to provide the source of protein in nutritional combinations according to the exemplary embodiments. Proteins suitable for use in the nutritional combinations 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 combination comprises a source of carbohydrates. In certain exemplary embodiments, the source of carbohydrates is present in an amount sufficient to provide about 10 to about 100 grams of carbohydrates per serving. The source of carbohydrates may be from one carbohydrate or more than one carbohydrate. In certain exemplary embodiments, the nutritional combinations comprise a source of carbohydrates in an amount sufficient to provide about 10 to about 40 grams, about 15 to about 35 grams, about 25 to about 35 grams, or about 28 to about 32 grams of carbohydrates per serving. Alternatively, the amount of carbohydrates present in the combination may be expressed in terms of percentage of carbohydrates by dry weight of the combination (wt%). In such instances, the combinations may comprise a source of carbohydrates in an amount sufficient to provide from 20 to 70 wt% carbohydrates by dry weight of the combination, preferably from 30 to 60 wt%, more preferably from 40 to 60 wt%, and most preferably from 50 to 60 wt%.

Carbohydrates used in the embodiments disclosed herein 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 combinations and is otherwise compatible with any other selected ingredient or feature present in the nutritional combination. Non-limiting examples of a source of carbohydrates which may be suitable for use in the exemplary nutritional combinations 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.

In certain exemplary embodiments, the nutritional combination comprises a source of fructooligosaccharides (FOS). The FOS, in certain exemplary embodiments, may be natural or synthetic, short-chain or long-chain, and combinations thereof. Natural sources of FOS include, but are not limited to, Jerusalem artichoke, chicory root, yacon, bananas, onions, garlic, asparagus, barley, wheat, jicama, and leeks. Suitable synthetic sources of FOS include Actilight® (Beghin-Meiji, Marckolsheim, France) and scFOS® (Ingredion, Inc., Westchester, Illinois). In certain exemplary embodiments, the nutritional combinations comprise a source of FOS in an amount sufficient to provide about 50 mg to about 1.5 grams, about 100 mg to about 500 mg, or about 150 mg to about 300 mg of FOS per serving. Alternatively, the amount of FOS present in the combination may be expressed in terms of percentage of FOS by dry weight of the combination (wt%). In such instances, the combinations may comprise FOS in an amount sufficient to provide from 0.1 to 2 wt% FOS by dry weight of the composition, preferably from 0.2 to 1 wt%, and most preferably from 0.3 to 0.6 wt%.

In certain exemplary embodiments, the nutritional combination comprises a source of fat. In certain exemplary embodiments, the source of fat is present in an amount sufficient to provide about 5 to about 20 grams or about 5 to about 15 grams of fat per serving.

Alternatively, the amount of fat present in the combination may be expressed in terms of percentage of fat by dry weight of the combination (wt%). In such instances, the

combinations may comprise fat in an amount sufficient to provide from 5 to 50 wt% fat by dry weight of the combination, preferably from 10 to 30 wt%, more preferably from 10 to 20 wt%, and most preferably from 12 to 18 wt%.

Non-limiting examples of fats suitable for use in the exemplary nutritional combinations 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.

ln certain preferred embodiments, the combination is a nutritional composition comprising: from 1 to 2 wt% HMB;
from 0.5 to 1.5 wt% THC;
a source of protein in an amount sufficient to provide from 10 to 30 wt% protein; a source of carbohydrates in an amount sufficient to provide from 30 to 60 wt% carbohydrates; and
a source of fat in an amount sufficient to provide from 10 to 30 wt% fat;
all by dry weight of the composition.

CLAIMS

1. A pharmaceutical or nutritional combination comprising beta-hydroxy beta-methylbutyrate (HMB) and tetrahydrocurcumin (THC).

2. The combination according to claim 1 , wherein the combination has a weight ratio of HMB to THC of from 1 :1 to 3:1.

3. The combination according to claim 1 or claim 2, wherein the combination comprises from 0.5 to 1.5 wt% THC by dry weight of the combination.

4. The combination according to any of the preceding claims, wherein the combination comprises from 1 to 2 wt% HMB by dry weight of the combination.

5. The combination according to any of the preceding claims, wherein the HMB and THC are provided in separate compositions.

6. The combination according to any of claims 1 to 4, wherein the HMB and THC are provided in a single composition.

7. A method of manufacturing the combination according to claim 6, comprising mixing a source of HMB with a source of THC.

8. A method of treatment of a subject by therapy, the method comprising administering to the subject a combination according to any of claims 1 to 6.

9. The combination of any of claims 1 to 6 for use in a method of treatment of a subject by therapy.

10. A method of attenuating muscle protein degradation and/or maintaining lean body mass in a subject in need thereof, the method comprising administering to the subject a combination according to any of claims 1 to 6.

1 1 . The combination according to any of claims 1 to 6 for use in method of attenuating muscle protein degradation and/or maintaining lean body mass in a subject in need thereof.

12. The method according to claim 8 or claim 10, or the combination for use according to claim 9 or claim 1 1 , wherein the subject in need thereof is an elderly human.

13. The method according to any of claims 8, 10 or 12, or the combination for use according to any of claims 9, 1 1 or 12, wherein the subject in need thereof is suffering from sarcopenia or a muscle wasting disease.

14. The method according to any of claims 8, 10, 12 or 13, or the combination for use according to any of claims 9 or 1 1-13, wherein the combination is administered to a human subject such that the amount of THC consumed by the subject ranges from about 10 mg/kg/day to about 25 mg/kg/day.

15. The method according to any of claims 8, 10 or 12 to 14, or the combination for use according to any of claims 9 or 1 1-14, wherein the combination is administered to a human subject such that the amount of HMB consumed by the subject ranges from about 20 mg/kg/day to about 30 mg/kg/day.